Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme

ABSTRACT

The present invention relates to inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme and their use in treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, central nervous system disorders, and diseases and conditions that are related to excessive glucocorticoids.

This is a divisional of U.S. patent application No. 12/390,286, filedFeb. 20, 2009, now U.S. Pat. No. 8,198,331, which is acontinuation-in-part of U.S. patent application No. 11/733,636, filed onApr. 10, 2007, now U.S. Pat. No. 7,528,282, which is acontinuation-in-part of U.S. patent application No. 11/326,277, filed onJan. 5, 2006, now U.S. Pat. No. 7,217,838, which claims priority to U.S.patent application No. 60/641,496, filed on Jan. 5, 2005, the entirecontents of all of which are fully incorporated herein by reference. Inaddition, U.S. patent application No. 12/390,286, filed on Feb. 20,2009, now U.S. Pat. No. 8,198,331, is a continuation-in-part of U.S.patent application No. 12/195,937, filed on Aug. 21, 2008, which claimspriority to U.S. patent application No. 60/957,082, filed on Aug. 21,2007, the entire contents of all of which are fully incorporated hereinby reference.

FIELD OF INVENTION

The present invention relates to compounds that are inhibitors of the11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The presentinvention further relates to the use of inhibitors of11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment ofnon-insulin dependent type 2 diabetes, insulin resistance, obesity,lipid disorders, metabolic syndrome, disorders and deficits of thecentral nervous system associated with diabetes, associated with agingand neurodegeneration, comprising attention deficit disorder in general,attention deficit hyperactivity disorder (ADHD), Alzheimer's disease(AD), mild cognitive impairment, senile dementia, AIDS dementia,neurodegeneration, depression, and schizophrenia, and other diseases andconditions that are mediated by excessive glucocorticoid action.

BACKGROUND OF THE INVENTION

Insulin is a hormone that modulates glucose and lipid metabolism.Impaired action of insulin (i.e., insulin resistance) results in reducedinsulin-induced glucose uptake, oxidation and storage, reducedinsulin-dependent suppression of fatty acid release from adipose tissue(i.e., lipolysis) and reduced insulin-mediated suppression of hepaticglucose production and secretion. Insulin resistance frequently occursin diseases that lead to increased and premature morbidity andmortality.

Diabetes mellitus is characterized by an elevation of plasma glucoselevels (hyperglycemia) in the fasting state or after administration ofglucose during a glucose tolerance test. While this disease may becaused by several underlying factors, it is generally grouped into twocategories, Type 1 and Type 2 diabetes. Type 1 diabetes, also referredto as Insulin Dependent Diabetes Mellitus (“IDDM”), is caused by areduction of production and secretion of insulin. In type 2 diabetes,also referred to as non-insulin dependent diabetes mellitus, or NIDDM,insulin resistance is a significant pathogenic factor in the developmentof hyperglycemia. Typically, the insulin levels in type 2 diabetespatients are elevated (i.e., hyperinsulinemia), but this compensatoryincrease is not sufficient to overcome the insulin resistance.Persistent or uncontrolled hyperglycemia in both type 1 and type 2diabetes mellitus is associated with increased incidence ofmacrovascular and/or microvascular complications includingatherosclerosis, coronary heart disease, peripheral vascular disease,stroke, nephropathy, neuropathy and retinopathy.

Insulin resistance, even in the absence of profound hyperglycemia, is acomponent of the metabolic syndrome. Recently, diagnostic criteria formetabolic syndrome have been established. To qualify a patient as havingmetabolic syndrome, three out of the five following criteria must bemet: elevated blood pressure above 130/85 mmHg, fasting blood glucoseabove 110 mg/dl, abdominal obesity above 40″ (men) or 35″ (women) waistcircumference and blood lipid changes as defined by an increase intriglycerides above 150 mg/dl or decreased HDL cholesterol below 40mg/dl (men) or 50 mg/dl (women). It is currently estimated that 50million adults, in the US alone, fulfill these criteria. Thatpopulation, whether or not they develop overt diabetes mellitus, are atincreased risk of developing the macrovascular and microvascularcomplications of type 2 diabetes listed above.

Available treatments for type 2 diabetes have recognized limitations.Diet and physical exercise can have profound beneficial effects in type2 diabetes patients, but compliance is poor. Even in patients havinggood compliance, other forms of therapy may be required to furtherimprove glucose and lipid metabolism.

One therapeutic strategy is to increase insulin levels to overcomeinsulin resistance. This may be achieved through direct injection ofinsulin or through stimulation of the endogenous insulin secretion inpancreatic beta cells. Sulfonylureas (e.g., tolbutamide and glipizide)or meglitinide are examples of drugs that stimulate insulin secretion(i.e., insulin secretagogues) thereby increasing circulating insulinconcentrations high enough to stimulate insulin-resistant tissue.However, insulin and insulin secretagogues may lead to dangerously lowglucose concentrations (i.e., hypoglycemia). In addition, insulinsecretagogues frequently lose therapeutic potency over time.

Two biguanides, metformin and phenformin, may improve insulinsensitivity and glucose metabolism in diabetic patients. However, themechanism of action is not well understood. Both compounds may lead tolactic acidosis and gastrointestinal side effects (e.g., nausea ordiarrhea).

Alpha-glucosidase inhibitors (e.g., acarbose) may delay carbohydrateabsorption from the gut after meals, which may in turn lower bloodglucose levels, particularly in the postprandial period. Likebiguanides, these compounds may also cause gastrointestinal sideeffects.

Glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a newer class ofcompounds used in the treatment of type 2 diabetes. These agents mayreduce insulin resistance in multiple tissues, thus lowering bloodglucose. The risk of hypoglycemia may also be avoided. Glitazones modifythe activity of the Peroxisome Proliferator Activated Receptor (“PPAR”)gamma subtype. PPAR is currently believed to be the primary therapeutictarget for the main mechanism of action for the beneficial effects ofthese compounds. Other modulators of the PPAR family of proteins arecurrently in development for the treatment of type 2 diabetes and/ordyslipidemia. Marketed glitazones suffer from side effects includingbodyweight gain and peripheral edema.

Additional treatments to normalize blood glucose levels in patients withdiabetes mellitus are needed. Other therapeutic strategies are beingexplored. For example, research is being conducted concerningGlucagon-Like Peptide 1 (“GLP-1”) analogues and inhibitors of DipeptidylPeptidase IV (“DPP-IV”) that increase insulin secretion. Other examplesinclude: Inhibitors of key enzymes involved in the hepatic glucoseproduction and secretion (e.g., fructose-1,6-bisphosphatase inhibitors)and direct modulation of enzymes involved in insulin signaling (e.g.,Protein Tyrosine Phosphatase-1B, or “PTP-1B”).

Another method of treating or prophylactically treating diabetesmellitus includes using inhibitors of 11-β-hydroxysteroid dehydrogenaseType 1 (11β-HSD1). Such methods are discussed in J. R. Seckl et al.,Endocrinology, 142: 1371-1376, 2001 and references cited therein.Glucocorticoids are steroid hormones that are potent regulators ofglucose and lipid metabolism. Excessive glucocorticoid action may leadto insulin resistance, type 2 diabetes, dyslipidemia, increasedabdominal obesity and hypertension. Glucocorticoids circulate in theblood in an active form (i.e., cortisol in humans) and an inactive form(i.e., cortisone in humans). 11β-HSD1, which is highly expressed inliver and adipose tissue, converts cortisone to cortisol leading tohigher local concentration of cortisol. Inhibition of 11β-HSD1 preventsor decreases the tissue specific amplification of glucocorticoid actionthus imparting beneficial effects on blood pressure and glucose- andlipid-metabolism.

11β-HSD-1 is a low affinity enzyme with K_(m) for cortisone in themicromolar range that prefers NADPH/NADP⁺ (nicotinamide adeninedinucleotide phosphate) as cofactors. 11β-HSD-1 is widely expressed andparticularly high expression levels are found in liver, brain, lung,adipose tissue, and vascular smooth muscle cells. In vitro studiesindicate that 11β-HSD-1 is capable of acting both as a reductase and adehydrogenase. However, many studies have shown that it functionsprimarily as a reductase in vivo and in intact cells. It convertsinactive 11-ketoglucocorticoids (i.e., cortisone ordehydrocorticosterone) to active 11-hydroxyglucocorticoids (i.e.,cortisol or corticosterone), and thereby amplifies glucocorticoid actionin a tissue-specific manner.

11β-HSD-1 is expressed in mammalian brain, and published data indicatesthat elevated levels of glucocorticoids may cause neuronal degenerationand dysfunction, particularly in the aged (de Quervain et al., Hum MolGenet., 13, 47-52 (2004); Belanoff et al. J. Psychiatr Res., 35, 127-35,(2001)). Evidence in rodents and humans suggests that prolongedelevation of plasma glucocorticoid levels impairs cognitive functionthat becomes more profound with aging. (A. M. Issa et al., J. Neurosci.,10, 3247-3254 (1990); S. J. Lupien et. al., Nat. Neurosci., 1, 69-73(1998); J. L. Yau et al., Neuroscience, 66, 571-581 (1995)). Chronicexcessive cortisol levels in the brain may result in neuronal loss andneuronal dysfunction. (D. S. Kerr et al., Psychobiology, 22, 123-133(1994); C. Woolley, Brain Res., 531, 225-231, (1990); P. W. Landfield,Science, 272, 1249-1251 (1996)). Furthermore, glucocorticoid-inducedacute psychosis exemplifies a more pharmacological induction of thisresponse, and is of major concern to physicians when treating patientswith these steroidal agents (Wolkowitz et al.; Ann NY Acad Sci., 1032,191-194 (2004)). It has been recently shown that 11β-HSD-1 mRNA isexpressed in human hippocampus, frontal cortex and cerebellum, and thattreatment of elderly diabetic individuals with the non-selective11β-HSD-1 and 11β-HSD-2 inhibitor carbenoxolone improved verbal fluencyand memory (Thekkapat et al., Proc Natl Acad Sci USA, 101, 6743-6749(2004)). Excessive glucocorticoid levels also affects psychopathology,as shown in animal models, it leads to increased anxiety and aggression.Chronic elevation of cortisol has been also associated with depressionin Cushing's disease (McEwen, Metab. Clin. & Exp., 54, 20-23 (2005)). Anumber of animal and clinical studies have provided evidence for thecorrelation between increases in glucocorticoid levels andneuropsychiatric disorders such as major depressive disorder, psychoticdepression, anxiety, panic disorder, post traumatic stress disorder, anddepression in Cushing's syndrome (Budziszewska, Polish J. of Pharmacol.,54, 343-349, (2002); Ströhle et al., Pharmacopsychiatry Vol. 36,S207-S214, 2003; DeBattista et al., TRENDS in Endocr. Metab., 17,117-120 (2006); Norman et al., Expert Rev. Neurotherapeutics, Vol. 7,pages 203-213 (2007)).

Thus, inhibiting 11β-HSD1 benefits patients suffering from non-insulindependent type 2 diabetes, insulin resistance, obesity, lipid disorders,metabolic syndrome, central nervous system disorders, age-related orglucocorticoid-related declines in cognitive function such as those seenin Alzheimer's and associated dementias, major depressive disorder,psychotic depression, anxiety, panic disorder, post traumatic stressdisorder, depression in Cushing's syndrome, and treatment resistantdepression, and other diseases and conditions mediated by excessiveglucocorticoid action.

SUMMARY OF THE INVENTION

All patents, patent applications and literature references cited in thespecification are herein incorporated by reference in their entirety.

One aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof

wherein

one of A¹, A², A³ and A⁴ is selected from the group consisting ofalkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, aryl carbonyl, arylsulfonyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl,heterocyclesulfonyl, aryl¹, arylalkyl, aryloxyalkyl, carboxyalkyl,carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl,—S(O)₂—N(R⁵R⁶), —NR⁷—[C(R⁸, R⁹)]_(n)—C(O)—R¹⁰, —O—[C(R¹¹R¹²)]—C(O)—R¹³,—OR^(14a), —N(R¹⁵R¹⁶), —CO₂R¹⁷, —C(O)—N(R¹⁸R¹⁹), —C(R²⁰R²¹)—OR²²,—C(R²³R²⁴)—N(R²⁵R²⁶), and heterocycle, with the exception that 5membered heterocycles may not contain two oxygen atoms, and theremaining members of the group consisting of A¹, A², A³ and A⁴ are eachindividually selected from the group consisting of hydrogen, alkyl,alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl,carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heteroaryl,heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl,heterocycleoxyalkyl, —S(O)₂—N(R⁵R⁶), —NR⁷—[C(R⁸R⁹)]_(n)—C(O)—R¹⁰,—O—[C(R¹¹R¹²)]_(p)—C(O)—R¹³, —OR^(14b), —N(R¹⁵R¹⁶), —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), —C(R²⁰R²¹)—OR²², and —C(R²³R²⁴)—. N(R²⁵R²⁶);

n is 0 or 1;

p is 0 or 1;

D is selected from the group consisting of a bond, —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—;

E is selected from the group consisting of a cycloalkyl, alkyl, aryl,heteroaryl and heterocycle, wherein the heteroaryl and the heterocycleare appended to the parent molecular moiety through an available carbonatom, or R⁴ and E together with the atoms to which they are attachedform a ring selected from the group consisting of cycloalkyl andheterocycle;

X is selected from the group consisting of a bond, —N(R³¹)—, —O—, —S—,—S(O)— and —S(O)₂—;

R¹ is selected from the group consisting of hydrogen and alkyl;

R² is selected from the group consisting of hydrogen, alkyl andcycloalkyl;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle andheterocyclealkyl, or R³ and R⁴ together with the atom to which they areattached form a ring selected from the group consisting of cycloalkyland heterocycle;

R⁵ and R⁶ are each independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, carboxy,carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy,cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl,aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl,heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl,heterocycleoxy, heterocyclesulfonyl and hydroxy, or R⁵ and R⁶ togetherwith the atom to which they are attached form a heterocycle;

R⁷ is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen and alkyl, or R⁸ and R⁹ taken together with the atom to whichthey are attached form a ring selected from the group consisting ofcycloalkyl and heterocycle;

R¹⁰ is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and —N(R³²R³³);

R¹¹ and R¹² are each independently selected from the group consisting ofhydrogen and alkyl or R¹¹ and R¹² taken together with the atom to whichthey are attached form a ring selected from the group consisting ofcycloalkyl and heterocycle;

R¹³ is selected from the group consisting of hydroxy and —N(R³⁴R³⁵);

R^(14a) is selected from the group consisting of carboxyalkyl,cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,heterocyclealkyl and heterocycleoxyalkyl;

R^(14b) is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl;

R¹⁵ and R¹⁶ are each independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl,carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl,aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl,heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocycleoxyalkyl, heterocyclesulfonyl, alkylsulfonyl,cycloalkylsulfonyl and arylsulfonyl, or R¹⁵ and R¹⁶ together with theatom to which they are attached form a heterocycle;

R¹⁷ is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl,heterocycle, heterocyclealkyl and heterocycleoxyalkyl;

R¹⁸ and R¹⁹ are each independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylsulfonyl, carboxy, carboxyalkyl,carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl,arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl,heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,heterocyclesulfonyl and hydroxy, or R¹⁸ and R¹⁹ together with the atomto which they are attached form a heterocycle;

R²⁰, R²¹ and R²² are each independently selected from the groupconsisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl,carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heterocycle and heterocyclealkyl;

R²³ and R²⁴ are each independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl,arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl,heteroarylsulfonyl, heterocycle, heterocyclecarbonyl andheterocyclesulfonyl;

R²⁵ and R²⁶ are each independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkyl carbonyl, alkylsulfonyl, aryl,arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl,cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl,heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl,heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyland hydroxy, or R²⁵ and R²⁶ together with the nitrogen to which they areattached form a ring selected from the group consisting of heteroaryland heterocycle;

R²⁷ and R²⁸ are each independently selected from the group consisting ofhydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R²⁷ andR²⁸ together with the atom to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle, or R²⁷and R²⁹ together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle, or R²⁸and R⁴ together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle;

R²⁹ and R³⁰ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy,heteroaryl, heterocycle, and —N(R³⁶R³⁷), or R²⁹ and R³⁰ together withthe atom to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle, or R²⁹ and R⁴ together withthe atoms to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle, or R²⁹ and E together with theatoms to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle;

R³¹ is selected from the group consisting of hydrogen, alkyl, aryl,cycloalkyl, heterocycle and heteroaryl, or R³¹ and E together with theatom to which they are attached form a ring selected from the groupconsisting of heteroaryl and heterocycle, or R³¹ and R⁴ together withthe atoms to which they are attached form a heterocycle;

R³² and R³³ are each independently selected from the group consisting ofhydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy,carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy,alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, andheterocyclesulfonyl, or R³² and R³³ together with the atom to which theyare attached form a heterocycle;

R³⁴ and R³⁵ are each independently selected from the group consisting ofhydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy,carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy,alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, andheterocyclesulfonyl, or R³⁴ and R³⁵ together with the atom to which theyare attached form a heterocycle; and

R³⁶ and R³⁷ are each independently selected from the group consisting ofhydrogen, alkyl and aryl.

A further aspect of the present invention encompasses the use of thecompounds of formula (I) for the treatment of disorders that aremediated by 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme, such asnon-insulin dependent type 2 diabetes, insulin resistance, obesity,lipid disorders, metabolic syndrome and other diseases and conditionsthat are mediated by excessive glucocorticoid action, comprisingadministering a therapeutically effective amount of a compound offormula (I).

According to still another aspect, the present invention is directed toa pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) in combination with apharmaceutically suitable carrier.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the results of memory consolidation in treated anduntreated mice measured as Mean Transfer Latency.

FIG. 2 depicts amount of phosphorylation of CREB in treated anduntreated mice.

FIG. 3 shows the results of memory consolidation in treated anduntreated mice measured as Mean Transfer Latency.

FIG. 4 shows the results of short memory retention in treated anduntreated mice measured as Mean Transfer Latency.

FIGS. 5 a-5 c show REM episodes, time and latency to first episode,respectively, on rat treated with an exemplary 11β-HSD-1 inhibitor.

FIGS. 6 a, 6 b and 6 c show the effects of an exemplary 11β-HSD-1inhibitor on cortical and hippocampal Ach release.

FIGS. 7 a and 7 b show the effects of an exemplary 11β-HSD-1 inhibitoron cortical and hippocampal 5-HT release.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof

wherein

one of A¹, A², A³ and A⁴ is selected from the group consisting ofalkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl,heterocyclesulfonyl, aryl¹, arylalkyl, aryloxyalkyl, carboxyalkyl,carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl,—S(O)₂—N(R⁵R⁶), —NR⁷—[C(R⁸R⁹)]_(a)—C(O)—R¹⁰,—O—[C(R¹¹R¹²)]_(p)—C(O)—R¹³, —OR^(14a), —N(R¹⁵R¹⁶), —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), —C(R²⁰R²¹)—OR²², —C(R²³R²⁴)—N(R²⁵R²⁶), and heterocycle,with the exception that 5 membered heterocycles may not contain twooxygen atoms, and the remaining members of the group consisting of A¹,A², A³ and A⁴ are each individually selected from the group consistingof hydrogen, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl,cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl,arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl,aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxyalkyl, —S(O)₂—N(R⁵R⁶),—NR⁷—[C(R⁸R⁹)]_(n)—C(O)—R¹⁰, —O—[C(R¹¹R¹²)]_(p)—C(O)—R¹³, —OR^(14b),—N(R¹⁵R¹⁶), —CO₂R¹⁷, —C(O)—N(R¹⁸R¹⁹), —C(R²⁰R²¹)—OR²², and—C(R²³R²⁴)—N(R²⁵R²⁶);

n is 0 or 1;

p is 0 or 1;

D is selected from the group consisting of a bond, —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—;

E is selected from the group consisting of a cycloalkyl, alkyl, aryl,heteroaryl and heterocycle, wherein the heteroaryl and the heterocycleare appended to the parent molecular moiety through an available carbonatom, or R⁴ and E together with the atoms to which they are attachedform a ring selected from the group consisting of cycloalkyl andheterocycle;

X is selected from the group consisting of a bond, —N(R³¹)—, —O—, —S—,—S(O)— and —S(O)₂—;

R¹ is selected from the group consisting of hydrogen and alkyl;

R² is selected from the group consisting of hydrogen, alkyl andcycloalkyl;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle andheterocyclealkyl, or R³ and R⁴ together with the atom to which they areattached form a ring selected from the group consisting of cycloalkyland heterocycle;

R⁵ and R⁶ are each independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, carboxy,carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy,cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl,aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl,heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl,heterocycleoxy, heterocyclesulfonyl and hydroxy, or R⁵ and R⁶ togetherwith the atom to which they are attached form a heterocycle;

R⁷ is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen and alkyl, or R⁸ and R⁹ taken together with the atom to whichthey are attached form a ring selected from the group consisting ofcycloalkyl and heterocycle;

R¹⁰ is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and —N(R³²R³³);

R¹¹ and R¹² are each independently selected from the group consisting ofhydrogen and alkyl or R¹¹ and R¹² taken together with the atom to whichthey are attached form a ring selected from the group consisting ofcycloalkyl and heterocycle;

R¹³ is selected from the group consisting of hydroxy and —N(R³⁴R³⁵);

R^(14a) is selected from the group consisting of carboxyalkyl,cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,heterocyclealkyl and heterocycleoxyalkyl;

R^(14b) is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl;

R¹⁵ and R¹⁶ are each independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl,carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl,aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl,heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocycleoxyalkyl, heterocyclesulfonyl, alkylsulfonyl,cycloalkylsulfonyl and arylsulfonyl, or R¹⁵ and R¹⁶ together with theatom to which they are attached form a heterocycle;

R¹⁷ is selected from the group consisting of hydrogen, alkyl,carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl,heterocycle, heterocyclealkyl and heterocycleoxyalkyl;

R¹⁸ and R¹⁹ are each independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylsulfonyl, carboxy, carboxyalkyl,carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl,arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl,heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,heterocyclesulfonyl and hydroxy, or R¹⁸ and R¹⁹ together with the atomto which they are attached form a heterocycle;

R²⁰, R²¹ and R²² are each independently selected from the groupconsisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl,carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heterocycle and heterocyclealkyl;

R²³ and R²⁴ are each independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl,arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl,heteroarylsulfonyl, heterocycle, heterocyclecarbonyl andheterocyclesulfonyl;

R²⁵ and R²⁶ are each independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, aryl,arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl,cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl,heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl,heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyland hydroxy, or R²⁵ and R²⁶ together with the nitrogen to which they areattached form a ring selected from the group consisting of heteroaryland heterocycle;

R²⁷ and R²⁸ are each independently selected from the group consisting ofhydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R²⁷ andR²⁸ together with the atom to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle, or R²⁷and R²⁹ together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle, or R²⁸and R⁴ together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle;

R²⁹ and R³⁰ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy,heteroaryl, heterocycle, and —N(R³⁶R³⁷), or R²⁹ and R³⁰ together withthe atom to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle, or R²⁹ and R⁴ together withthe atoms to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle, or R²⁹ and E together with theatoms to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle;

R³¹ is selected from the group consisting of hydrogen, alkyl, aryl,cycloalkyl, heterocycle and heteroaryl, or R³¹ and E together with theatom to which they are attached form a ring selected from the groupconsisting of heteroaryl and heterocycle, or R³¹ and R⁴ together withthe atoms to which they are attached form a heterocycle;

R³² and R³³ are each independently selected from the group consisting ofhydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy,carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy,alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, andheterocyclesulfonyl, or R³² and R³³ together with the atom to which theyare attached form a heterocycle;

R³⁴ and R³⁵ are each independently selected from the group consisting ofhydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy,carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy,alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, andheterocyclesulfonyl, or R³⁴ and R³⁵ together with the atom to which theyare attached form a heterocycle; and

R³⁶ and R³⁷ are each independently selected from the group consisting ofhydrogen, alkyl and aryl.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof,

wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen; and A¹, R³, R⁴, D and E are as described in thesummary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is a bond; and A¹, R³, R⁴ and E are as described in the summary of theinvention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is a bond;

E is selected from the group consisting of alkyl, aryl, and heteroaryl;and

A¹, R³, and R⁴ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is a bond;

E is selected from the group consisting of alkyl, aryl and heteroaryl;

R³ and R⁴ are hydrogen; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is a bond;

E is selected from the group consisting of alkyl, aryl and heteroaryl;

R³ is hydrogen;

R⁴ is alkyl; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof;

wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is a bond;

E is selected from the group consisting of alkyl, aryl and heteroaryl;

R³ and R⁴ are alkyl; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is a bond;

E is selected from the group consisting of alkyl, aryl and heteroaryl;

R³ and R⁴ together with the atom to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle; and A¹is as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof;

wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is a bond;

E is selected from the group consisting of alkyl, aryl and heteroaryl;

R³ and R⁴ together with the atom to which they are attached form acycloalkyl ring; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is a bond;

E is selected from the group consisting of alkyl, aryl and heteroaryl;

R³ and R⁴ together with the atom to which they are attached, form aheterocycle ring; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl and —S(O)₂—N(R⁵R⁶); wherein. R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is a bond;

R⁴ and E together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl and —S(O)₂—N(R⁵, R⁶); wherein R³, R⁵, R⁶,R¹⁷, R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (II), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof,

wherein

t is 1 or 2;

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ is alkyl;

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention; and

R³⁸ is selected from the group consisting of arylalkyl andheteroarylalkyl wherein the aryl of the arylalkyl and the heteroaryl ofthe heteroarylalkyl are each independently unsubstituted or substitutedwith 1, 2 or 3 substituents selected from the group consisting of alkyl,halogen and haloalkyl.

Another aspect of the present invention is directed toward a compound offormula (III), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof,

wherein

t is 1 or 2;

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

R³ is alkyl;

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention; and

R³⁸ is selected from the group consisting of arylalkyl andheteroarylalkyl wherein the aryl of the arylalkyl and the heteroaryl ofthe heteroarylalkyl are each independently unsubstituted or substitutedwith 1, 2 or 3 substituents selected from the group consisting of alkyl,halogen and haloalkyl.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁴)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; and R²⁷, R²⁸, R²⁹, R³⁰, X, A¹, R³, R⁴ and E areas described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and X are as describedin the summary of the invention;

E is selected from the group consisting of aryl and heteroaryl; and A¹,R³, and R⁴ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are as describedin the summary of the invention;

E is selected from the group consisting of aryl and heteroaryl;

X is a bond; and A¹, R³, and R⁴ are as described in the summary of theinvention. Another aspect of the present invention is directed toward acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,salt of a prodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is a bond;

R³ and R⁴ are hydrogen; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is a bond;

R³ is hydrogen;

R⁴ is alkyl; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is a bond;

R³ and R⁴ are alkyl; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are as describedin the summary of the invention;

E is selected from the group consisting of aryl and heteroaryl;

X is a bond;

R³ and R⁴ together with the atom to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle; and A¹is as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is a bond;

R³ and R⁴ together with the atom to which they are attached form acycloalkyl ring; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ is and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸) X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is a bond;

R³ and R⁴ together with the atom to which they are attached form aheterocycle ring; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are as describedin the summary of the invention;

E is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of —N(R³¹)— and —O—; and A¹, R³,and R⁴ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of —N(R³¹)— and —O—;

R³ and R⁴ are hydrogen; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of —N(R³¹)— and —O—;

R³ is hydrogen;

R⁴ is alkyl; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of —N(R³¹)— and —O—;

R³ and R⁴ are alkyl; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of —N(R³¹)— and —O—;

R³ and R⁴ together with the atom to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, R²⁹, and R³⁰ are eachindependently selected from the group consisting of hydrogen and allyl;

E is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of —N(R³¹)— and —O—;

R³ and R⁴ together with the atom to which they are attached form acycloalkyl ring; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Another aspect of the present invention is directed toward a compound offormula (I), or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein

A², A³ and A⁴ are hydrogen;

R¹ and R² are hydrogen;

D is selected from the group consisting of —C(R²⁷R²⁸)—X— and—C(R²⁷R²⁸)—C(R²⁹R³⁰)—X—; wherein R²⁷, R²⁸, and R³⁰ are eachindependently selected from the group consisting of hydrogen and alkyl;

E is selected from the group consisting of aryl and heteroaryl;

X is selected from the group consisting of —N(R³¹)— and —O—;

R³ and R⁴ together with the atom to which they are attached form aheterocycle ring; and

A¹ is selected from the group consisting of heteroaryl, —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), alkylsulfonyl, and —S(O)₂—N(R⁵R⁶); wherein R⁵, R⁶, R¹⁷,R¹⁸ and R¹⁹ are as described in the summary of the invention.

Exemplary compounds of the present invention having formula (I) include,but are not limited to,

-   E-4-{([1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylic    acid;-   E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic    acid;-   E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic acid;-   E-4-({[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylic    acid amide;-   E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic    acid amide;-   E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic acid    amide;-   E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl)amino}adamantane-1-carboxamide;-   E-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-({[(1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxamide;-   E-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide;-   E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-{[2-methyl-2-(4-pyridin-4-ylphenyl)propanoyl]amino}adamantane-1-carboxamide;-   E-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-1-carboxamide;-   E-4-[(2-methyl-2-thien-3-ylpropanoyl)amino]adamantane-1-carboxamide;-   E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamantane-1-carboxamide;-   E-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}propanoyl)amino]adamantane-1-carboxamide;-   E-4-({[1-(4-methoxyphenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;-   E-4-{[2-(4-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-[5-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopiperidine-3-carboxamide;-   E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopyrrolidine-3-carboxamide;-   E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopyrrolidine-3-carboxamide;-   E-4-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3-carboxamide;-   E-4-(aminocarbonyl)-2-adamantyl]-1-(3-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3-carboxamide;-   E-4-({2-methyl-2-[4-(1-methyl-1-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-1-carboxamide;-   E-4-{[2-(3-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-({2-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxamide;-   E-4-{[2-methyl-2-(4-pyridin-3-ylphenyl)propanoyl]amino}adamantane-1-carboxamide;-   4-{[({(E)-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoic    acid;-   E-4-({2-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-1-carboxamide;-   E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(1-methyl-1-phenylethyl)-2-oxopyrrolidine-3-carboxamide;-   E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxamide;-   E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide;-   E-4-{[2-methyl-2-(1,3-thiazol-2-yl)propanoyl]amino}adamantane-1-carboxamide;-   E-4-(aminocarbonyl)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpiperidine-3-carboxamide;-   E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopiperidine-3-carboxamide;-   E-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxamide;-   E-4-{[2-(1-benzothien-3-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   E-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamide;-   (E)-4-[(2-methyl-2-pyrazin-2-ylpropanoyl)amino]adamantane-1-carboxamide;-   N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(2-pyridin-2-ylethyl)pyrrolidine-3-carboxamide;-   methyl(E)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxylate;-   (E)-4-({2-methyl-2-[3-(1,3-thiazol-4-ylmethoxy)phenyl]propanoyl}amino)adamantane-1-carboxamide;-   (E)-4-({2-methyl-2-[6-(methylamino)pyridin-3-yl]propanoyl}amino)adamantane-1-carboxamide;-   (E)-4-({2-methyl-2-[3-(morpholin-4-ylmethyl)phenyl]propanoyl}amino)adamantane-1-carboxamide;-   (E)-4-({2-methyl-2-[4-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamantane-1-carboxamide;-   (E)-4-[(2-{3-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-2-methylpropanoyl)amino]adamantane-1-carboxamide;-   methyl(E)-4-{[(1-phenylcyclopropyl)carbonyl]amino}adamantane-1-carboxylate;-   (E)-4-{[2-(6-fluoropyridin-3-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   (E)-N-[3-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;-   N-[(E)-5-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopiperidine-3-carboxamide;-   N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-4-ylmethyl)pyrrolidine-3-carboxamide;-   (E)-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxylic    acid;-   N-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-phenylcyclopropanecarboxamide;-   (E)-4-({3-[(5-cyanopyridin-2-yl)oxy]-2,2-dimethylpropanoyl}amino)adamantane-1-carboxamide;-   N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(1-pyridin-2-ylethyl)pyrrolidine-3-carboxamide;-   (E)-4-[(2-methyl-3-phenylpropanoyl)amino]adamantane-1-carboxamide;-   (E)-4-{[2-methyl-2-(6-morpholin-4-ylpyridin-3-yl)propanoyl]amino}adamantane-1-carboxamide;-   methyl(E)-4-({[1-(4-chlorophenyl)cyclobutyl]carbonyl}amino)adamantane-1-carboxylate;-   N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-3-ylmethyl)pyrrolidine-3-carboxamide;-   (E)-4-[(2-methyl-2-{6-[(2-morpholin-4-ylethyl)amino]pyridin-3-yl}propanoyl)amino]adamantane-1-carboxamide;-   (E)-4-[(2-methyl-2-{4-[(E)-2-pyridin-4-ylvinyl]phenyl}propanoyl)amino]adamantane-1-carboxamide;-   N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-chlorophenyl)-2-methylpropanamide;-   (E)-4-({2-methyl-2-[3-(2-morpholin-4-ylethoxy)phenyl]propanoyl}amino)adamantane-1-carboxamide;-   (E)-4-{[2-(3-cyanopyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   (E)-4-({2-methyl-2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanoyl}amino)adamantane-1-carboxamide;-   N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide;-   (E)-N-[4-(aminosulfonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;-   (E)-4-({2-methyl-2-[4-(pentyloxy)phenyl]propanoyl}amino)adamantane-1-carboxylic    acid;-   (E)-4-({2-methyl-2-[4-(1,3-thiazol-4-ylmethoxy)phenyl]propanoyl}amino)adamantane-1-carboxylic    acid;-   (E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(1,3-thiazol-5-ylmethyl)adamantane-1-carboxamide;-   (E)-4-({2-[4-(benzyloxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxylic    acid;-   (E)-4-{[2-(5-cyanopyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;-   (E)-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxylic    acid;-   4-[({[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)-1-adamantyl]carbonyl}amino)methyl]benzoic    acid;-   4-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoic    acid;-   3-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoic    acid;-   (E)-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylic    acid;-   (E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-4-ylmethyl)adamantane-1-carboxamide;-   (E)-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylic    acid;-   (E)-N-(2-furylmethyl)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;-   3-[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)-1-adamantyl]-1H-pyrazole-5-carboxamide;-   (E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-3-ylmethyl)adamantane-1-carboxamide;-   (E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-2-ylmethyl)adamantane-1-carboxamide;-   (E)-4-({2-[4-(cyclohexylmethoxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxylic    acid;-   (E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}propanoyl)amino]adamantane-1-carboxylic    acid; and-   N-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3-carboxamide.

Another embodiment of the present invention discloses a method ofinhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme,comprising administering to a mammal, a therapeutically effective amountof the compound of formula (I).

Another embodiment of the present invention discloses a method oftreating disorders in a mammal by inhibiting 11-beta-hydroxysteroiddehydrogenase Type I enzyme, comprising administering to a mammal, atherapeutically effective amount of the compound of formula (I).

Another embodiment of the present invention discloses a method oftreating non-insulin dependent type 2 diabetes in a mammal by inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme comprisingadministering to a mammal, a therapeutically effective amount of thecompound of formula (I).

Another embodiment of the present invention discloses a method oftreating insulin resistance in a mammal by inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme comprisingadministering to a mammal, a therapeutically effective amount of thecompound of formula (I).

Another embodiment of the present invention discloses a method oftreating obesity in a mammal by inhibiting 11-beta-hydroxysteroiddehydrogenase Type I enzyme comprising administering to a mammal, atherapeutically effective amount of the compound of formula (I).

Another embodiment of the present invention discloses a method oftreating lipid disorders in a mammal by inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme comprisingadministering to a mammal, a therapeutically effective amount of thecompound of formula (I).

Another embodiment of the present invention discloses a method oftreating metabolic syndrome in a mammal by inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme comprisingadministering to a mammal, a therapeutically effective amount of thecompound of formula (I).

Another embodiment of the present invention discloses a method oftreating diseases and conditions that are mediated by excessiveglucocorticoid action in a mammal by inhibiting 11-beta-hydroxysteroiddehydrogenase Type I enzyme comprising administering to a mammal, atherapeutically effective amount of the compound of formula (I).

Another embodiment of the present invention discloses a pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound of formula (I) in combination with a pharmaceutically suitablecarrier.

DEFINITION OF TERMS

The term “alkenyl” as used herein, refers to a straight or branchedchain hydrocarbon containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, refers to an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy andhexyloxy.

The term “alkoxyalkyl” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl and methoxymethyl.

The term “alkoxycarbonyl” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl and tert-butoxycarbonyl.

The term “alkyl” as used herein, refers to a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl andn-decyl.

The term “alkylcarbonyl,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.

The term “alkylsulfonyl” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkyl-NH” as used herein, refers to an alkyl group, as definedherein, appended to the parent molecular moiety through a nitrogen atom.

The term “alkyl-NH-alkyl” as used herein, refers to an alkyl-NH group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein.

The term “aryl” as used herein, means a phenyl group, or a bicyclic or atricyclic fused ring system. Bicyclic fused ring systems are exemplifiedby a phenyl group appended to the parent molecular moiety and fused to amonocyclic cycloalkyl group, as defined herein, a phenyl group, amonocyclic heteroaryl group, as defined herein, or a monocyclicheterocycle, as defined herein. Tricyclic fused ring systems areexemplified by an aryl bicyclic fused ring system, as defined herein andfused to a monocyclic cycloalkyl group, as defined herein, a phenylgroup, a monocyclic heteroaryl group, as defined herein, or a monocyclicheterocycle, as defined herein. Representative examples of aryl include,but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl,indenyl, naphthyl, phenyl and tetrahydronaphthyl.

The aryl groups of this invention may be optionally substituted with 1,2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylalkoxy,arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano,cyanoalkyl, cycloalkylalkoxy, ethylenedioxy, formyl, haloalkoxy,haloalkyl, halogen, heteroaryl, heteroarylalkenyl, heteroarylalkyl,heteroarylalkoxy, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclealkoxy, heterocyclecarbonyl, heterocycleoxy, hydroxy,hydroxyalkyl, nitro, R_(f)R_(g)N—, R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyland R_(f)R_(g)Nsulfonyl, wherein R_(f) and R_(g) are independentlyselected from the group consisting of hydrogen, alkyl, alkoxyalkyl,alkylcarbonyl, alkylsulfonyl, cycloalkyl, heterocyclealkyl andcycloalkylalkyl and wherein the cycloalkyl, the heterocycle ofheterocyclealkyl and the cycloalkyl of cycloalkylalkyl as represented byR_(f) and R_(g) are each independently unsubstituted or substituted with1, 2 or 3 substituent selected from the group consisting of alkyl,haloalkyl and halogen. The substituent aryl, the aryl of arylalkyl, thearyl of arylalkenyl, the aryl of arylalkoxy, the aryl of arylcarbonyl,the aryl of aryloxy, the aryl of arylsulfonyl, the cycloalkyl ofcycloalkylalkoxy, the substituent heteroaryl, the heteroaryl ofheteroarylalkyl, the heteroaryl of heteroarylalkenyl, the heteroaryl ofheteroarylalkoxy, the heteroaryl of heteroarylcarbonyl, the substituentheterocycle, the heterocycle of heterocyclealkyl, the heterocycle ofheterocyclealkoxy, the heterocycle of heterocyclecarbonyl, theheterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonylmay be optionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl,cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, R_(f)R_(g)N—,R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl and R_(f)R_(g)Nsulfonyl.

The term “aryl¹” as used herein, refers to a substituted phenyl groupwherein the substituent is a member selected from the group consistingof alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, aryl carbonyl,aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl,heteroaryl alkyl, heteroaryl carbonyl, heterocycle, heterocyclecarbonyl,heterocycleoxy, hydroxy, hydroxyalkyl and nitro, or a bicyclic or atricyclic fused ring system. Bicyclic fused ring systems are exemplifiedby a phenyl group appended to the parent molecular moiety, which isfused to a cycloalkyl group, as defined herein, a phenyl group, aheteroaryl, as defined herein, or a heterocycle as defined herein.Tricyclic fused ring systems are exemplified by an aryl bicyclic fusedring system fused to a cycloalkyl group, as defined herein, a phenylgroup, a heteroaryl, as defined herein, or a heterocycle as definedherein. Bicyclic and tricyclic fused ring systems of this invention maybe optionally substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl,aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano,cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen,heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle,heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro,R_(f)R_(g)N—, R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl andR_(f)R_(g)Nsulfonyl, wherein R_(f) and R_(g) are as described herein.Representative examples of aryl¹ include, but are not limited to,anisole, aniline, anthracenyl, azulenyl, fluorenyl, naphthyl, andtetrahydronaphthyl.

The term “arylalkenyl” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through analkenyl group, as defined herein.

The term “arylalkyl” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl and2-naphth-2-ylethyl.

The term “arylalkoxy” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein.

The term “arylcarbonyl” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofarylcarbonyl include, but are not limited to, benzoyl and naphthoyl.

The term “aryl-NH—” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through a nitrogen atom.

The term “aryl-NH-alkyl” as used herein, refers to an aryl-NH— group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “aryloxy,” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through an oxy moiety,as defined herein. Representative examples of aryloxy include, but arenot limited to phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy,4-methylphenoxy and 3,5-dimethoxyphenoxy.

The term “aryloxyalkyl” as used herein, refers to an aryloxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “arylsulfonyl” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofarylsulfonyl include, but are not limited to, phenylsulfonyl,4-bromophenylsulfonyl, and naphthylsulfonyl.

The term “carbonyl” as used herein refers to a —C(O)— group.

The term “carboxy” as used herein refers to a —C(O)—OH group.

The term “carboxyalkyl” as used herein refers to a carboxy group asdefined herein, appended to the parent molecular moiety through an alkylgroup as defined herein.

The term “carboxycycloalkyl” as used herein refers to a carboxy group asdefined herein, appended to the parent molecular moiety through ancycloalkyl group as defined herein.

The term “cycloalkyl” as used herein, refers to a monocyclic, bicyclic,or tricyclic ring system. Monocyclic ring systems are exemplified by asaturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms.Examples of monocyclic ring systems include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic fused ringsystems are exemplified by a cycloalkyl group appended to the parentmolecular moiety, which is fused to an additional cycloalkyl group, asdefined herein, a phenyl group, a heteroaryl, as defined herein, or aheterocycle as defined herein. Tricyclic fused ring systems areexemplified by a cycloalkyl bicyclic fused ring system fused to anadditional cycloalkyl group, as defined herein, a phenyl group, aheteroaryl, as defined herein, or a heterocycle as defined herein.Bicyclic ring systems are also exemplified by a bridged monocyclic ringsystem in which two non-adjacent carbon atoms of the monocyclic ring arelinked by an alkylene bridge of between one and three additional carbonatoms. Representative examples of bicyclic ring systems include, but arenot limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane andbicyclo[4.2.1]nonane. Tricyclic ring systems are also exemplified by abicyclic ring system in which two non-adjacent carbon atoms of thebicyclic ring are linked by a bond or an alkylene bridge of between oneand three carbon atoms. Representative examples of tricyclic-ringsystems include, but are not limited to, tricyclo[3.3.1.0^(3,7)]nonaneand tricyclo[3.3.1.1^(3,7)]decane (adamantane). The cycloalkyl groups ofthis invention may be substituted with 1, 2, 3, 4 or 5 substituentsindependently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl,aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy,carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl,haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,heterocycleoxy, hydroxy, hydroxyalkyl, nitro, R_(f)R_(g)N—,R_(f)R_(g)Nallyl, R_(f)R_(g)Ncarbonyl and R_(f)R_(g)Nsulfonyl, whereinR_(f) and R_(g) are independently selected from the group consisting ofhydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyland cycloalkylalkyl. The substituent aryl, the aryl of arylalkyl, thearyl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, thesubstituent heteroaryl, the heteroaryl of heteroarylalkyl, theheteroaryl of heteroarylcarbonyl, the substituent heterocycle, theheterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl,the heterocycle of heterocycleoxy, the heterocycle ofheterocyclesulfonyl may be optionally substituted with 0, 1, 2 or 3substituents independently selected from the group consisting of alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy,carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,R_(f)R_(g)N—, R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl andR_(f)R_(g)Nsulfonyl.

The term “cycloalkylalkyl” as used herein, refers to a cycloalkyl group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples ofcycloalkylalkyl include, but are not limited to, cyclopropylmethyl,2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and4-cycloheptylbutyl.

The term “cycloalkylalkoxy” as used herein, refers to a cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough an alkoxy group, as defined herein.

The term “cycloalkylcarbonyl” as used herein, refers to cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,2-cyclobutylcarbonyl and cyclohexylcarbonyl.

The term “cycloalkyloxy,” as used herein, refers to cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an oxygroup, as defined herein.

The term “cycloalkylsulfonyl,” as used herein, refers to cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples ofcycloalkylsulfonyl include, but are not limited to, cyclohexylsulfonyland cyclobutylsulfonyl.

The term “halo” or “halogen,” as used herein, refers to —Cl, —Br, —I or—F.

The term “haloalkyl,” as used herein, refers to at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicring or an aromatic bicyclic ring system. The aromatic monocyclic ringsare five or six membered rings containing at least one heteroatomindependently selected from the group consisting of N, O and S. The fivemembered aromatic monocyclic rings have two double bonds and the sixmembered aromatic monocyclic rings have three double bonds. The bicyclicheteroaryl groups are exemplified by a monocyclic heteroaryl ringappended to the parent molecular moiety and fused to a monocycliccycloalkyl group, as defined herein, a monocyclic aryl group, as definedherein, a monocyclic heteroaryl group, as defined herein, or amonocyclic heterocycle, as defined herein. Representative examples ofheteroaryl include, but are not limited to, benzimidazolyl,benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl,imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuranyl,isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,oxadiazolyl, oxazolyl, phthalazinyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, quinolizinyl,quinoxalinyl, quinazolinyl, tetrazolyl, thiadiazolyl, thiazolyl,thienyl, triazolyl and triazinyl.

The heteroaryls of this invention may be optionally substituted with 1,2 or 3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkynyl, aryl, arylalkenyl, arylalkyl, arylcarbonyl,aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,cycloalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen,heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle,heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy,hydroxyalkyl, nitro, R_(f)R_(g)N—, R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyland R_(f)R_(g)Nsulfonyl, wherein R_(f) and R_(g) are as describedherein. The substituent aryl, the aryl of arylalkyl, the aryl ofarylalkenyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl ofarylsulfonyl, the substituent heteroaryl, the heteroaryl ofheteroarylalkyl, the heteroaryl of heteroarylalkenyl, the substituentheterocycle, the heterocycle of heterocyclealkyl, the heterocycle ofheterocyclecarbonyl, the heterocycle of heterocycleoxy, may beoptionally substituted with 1, 2 or 3 substituents independentlyselected from the group consisting of alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl,cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, R_(f)R_(g)N—,R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl and R_(f)R_(g)Nsulfonyl.

The term “heteroarylalkenyl” as used herein, refers to a heteroaryl, asdefined herein, appended to the parent molecular moiety through analkenyl group, as defined herein.

The term “heteroarylalkyl” as used herein, refers to a heteroaryl, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “heteroarylalkoxy” as used herein, refers to a heteroaryl, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein.

The term “heteroaryloxy” as used herein, refers to a heteroaryl, asdefined herein, appended to the parent molecular moiety through an oxygroup, as defined herein.

The term “heteroaryloxyalkyl” as used herein, refers to a heteroaryloxy,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein.

The term “heterocycle” as used herein, refers to a non-aromaticmonocyclic ring or a non-aromatic bicyclic ring. The non-aromaticmonocyclic ring is a three, four, five, six, seven, or eight memberedring containing at least one heteroatom, independently selected from thegroup consisting of N, O and S. Representative examples of monocyclicring systems include, but are not limited to, azetidinyl, aziridinyl,diazepinyl, dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrothienyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone) and thiopyranyl. The bicyclic heterocycles areexemplified by a monocyclic heterocycle appended to the parent molecularmoiety and fused to a monocyclic cycloalkyl group, as defined herein, amonocyclic aryl group, a monocyclic heteroaryl group, as defined herein,or a monocyclic heterocycle, as defined herein. Bicyclic ring systemsare also exemplified by a bridged monocyclic ring system in which twonon-adjacent atoms of the monocyclic ring are linked by a bridge ofbetween one and three atoms selected from the group consisting ofcarbon, nitrogen and oxygen. Representative examples of bicyclic ringsystems include but are not limited to, for example, benzopyranyl,benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl,1,5-diazocanyl, 3,9-diaza-bicyclo[4.2.1]non-9-yl,3,7-diazabicyclo[3.3.1]nonane, octahydro-pyrrolo[3,4-c]pyrrole,indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-1H-benzo[c]azepine,2,3,4,5-tetrahydro-1H-benzo[b]azepine,2,3,4,5-tetrahydro-1H-benzo[d]azepine, tetrahydroisoquinolinyl andtetrahydroquinolinyl.

The heterocycles of this invention may be optionally substituted with 1,2 or 3 substituents independently selected from oxo, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy,arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy,formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl,heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy,hydroxy, hydroxyalkyl, nitro, R_(f)R_(g)N—, R_(f)R_(g)Nalkyl,R_(f)R_(g)Ncarbonyl and R_(f)R_(g)Nsulfonyl, wherein R_(f) and R_(g) areas described herein.

The substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl,the aryl of aryloxy, the aryl of arylsulfonyl, the heteroaryl, theheteroaryl of heteroarylalkyl, the substituent heterocycle, theheterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl,the heterocycle of heterocycleoxy, may be optionally substituted with 1,2 or 3 substituents independently selected from the group consisting ofalkoxy, alkoxyallyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl,carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl,nitro, R_(f)R_(g)N—, R_(f)R_(g)Nalkyl, R_(f)R_(g)Ncarbonyl andR_(f)R_(g)Nsulfonyl.

The term “heterocyclealkyl” as used herein, refers to a heterocycle, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heterocyclealkylinclude, but are not limited to, pyridin-3-ylmethyl and2-pyrimidin-2-ylpropyl.

The term “heterocyclealkylcarbonyl” as used herein, refers to aheterocyclealkyl, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein.

The term “heterocyclealkoxy” as used herein, refers to a heterocycle, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein.

The term “heterocycleoxy” as used herein, refers to a heterocycle, asdefined herein, appended to the parent molecular moiety through an oxygroup, as defined herein.

The term “heterocycleoxyalkyl” as used herein, refers to aheterocycleoxy, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein.

The term “heterocycle-NH—” as used herein, refers to a heterocycle, asdefined herein, appended to the parent molecular moiety through anitrogen atom.

The term “heterocycle-NH-alkyl” as used herein, refers to aheterocycle-NH—, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein.

The term “heterocyclecarbonyl” as used herein, refers to a heterocycle,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofheterocyclecarbonyl include, but are not limited to,1-piperidinylcarbonyl, 4-morpholinylcarbonyl, pyridin-3-ylcarbonyl andquinolin-3-ylcarbonyl.

The term “heterocyclesulfonyl” as used herein, refers to a heterocycle,as defined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofheterocyclesulfonyl include, but are not limited to,1-piperidinylsulfonyl, 4-morpholinylsulfonyl, pyridin-3-ylsulfonyl andquinolin-3-ylsulfonyl.

The term “hydroxy” as used herein, refers to an —OH group.

The term “hydroxyalkyl” as used herein, refers to a hydroxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of hydroxyalkylinclude, but are not limited to, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl and 2-ethyl-4-hydroxyheptyl.

The term “oxo” as used herein, refers to a ═O group.

The term “oxy” as used herein, refers to a —O— group.

The term “sulfonyl” as used herein, refers to a —S(O)₂— group.

The present compounds may exist as therapeutically suitable salts. Theterm “therapeutically suitable salt,” refers to salts or zwitterions ofthe compounds which are water or oil-soluble or dispersible, suitablefor treatment of disorders without undue toxicity, irritation andallergic response, commensurate with a reasonable benefit/risk ratio andeffective for their intended use. The salts may be prepared during thefinal isolation and purification of the compounds or separately byreacting an amino group of the compounds with a suitable acid. Forexample, a compound may be dissolved in a suitable solvent, such as butnot limited to methanol and water and treated with at least oneequivalent of an acid, like hydrochloric acid. The resulting salt mayprecipitate out and be isolated by filtration and dried under reducedpressure. Alternatively, the solvent and excess acid may be removedunder reduced pressure to provide the salt. Representative salts includeacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, isethionate, fumarate, lactate, maleate, methanesulfonate,naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,glutamate, para-toluenesulfonate, undecanoate, hydrochloric,hydrobromic, sulfuric, phosphoric and the like. The amino groups of thecompounds may also be quaternized with alkyl chlorides, bromides andiodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl,myristyl, stearyl and the like.

Basic addition salts may be prepared during the final isolation andpurification of the present compounds by reaction of a carboxyl groupwith a suitable base such as the hydroxide, carbonate, or bicarbonate ofa metal cation such as lithium, sodium, potassium, calcium, magnesium,or aluminum, or an organic primary, secondary, or tertiary amine.Quaternary amine salts derived from methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine,pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine and N,N′-dibenzylethylenediamine, ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like, arecontemplated as being within the scope of the present invention.

The present compounds may also exist as therapeutically suitableprodrugs. The term “therapeutically suitable prodrug,” refers to thoseprodrugs or zwitterions which are suitable for use in contact with thetissues of patients without undue toxicity, irritation and allergicresponse, are commensurate with a reasonable benefit/risk ratio and areeffective for their intended use. The term “prodrug,” refers tocompounds that are rapidly transformed in vivo to the parent compoundsof formula (I-IXc) for example, by hydrolysis in blood. The term“prodrug,” refers to compounds that contain, but are not limited to,substituents known as “therapeutically suitable esters.” The term“therapeutically suitable ester,” refers to alkoxycarbonyl groupsappended to the parent molecule on an available carbon atom. Morespecifically, a “therapeutically suitable ester,” refers toalkoxycarbonyl groups appended to the parent molecule on one or moreavailable aryl, cycloalkyl and/or heterocycle groups as defined herein.Compounds containing therapeutically suitable esters are an example, butare not intended to limit the scope of compounds considered to beprodrugs. Examples of prodrug ester groups include pivaloyloxymethyl,acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as othersuch groups known in the art. Other examples of prodrug ester groups arefound in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems,Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

Asymmetric centers may exist in the present compounds. Individualstereoisomers of the compounds are prepared by synthesis from chiralstarting materials or by preparation of racemic mixtures and separationby conversion to a mixture of diastereomers followed by separation orrecrystallization, chromatographic techniques, or direct separation ofthe enantiomers on chiral chromatographic columns. Starting materials ofparticular stereochemistry are either commercially available or are madeby the methods described hereinbelow and resolved by techniques wellknown in the art.

Geometric isomers may exist in the present compounds. The inventioncontemplates the various geometric isomers and mixtures thereofresulting from the disposal of substituents around a carbon-carbondouble bond, a cycloalkyl group, or a heterocycloalkyl group.Substituents around a carbon-carbon double bond are designated as beingof Z or E configuration and substituents around a cycloalkyl orheterocycloalkyl are designated as being of cis or trans configuration.Furthermore, the invention contemplates the various isomers and mixturesthereof resulting from the disposal of substituents around an adamantanering system. Two substituents around a single ring within an adamantanering system are designated as being of Z or E relative configuration.For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. leNoble J. Org. Chem. 63: 2758-2760, 1998.

Preparation of Compounds of the Invention

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes andExperimentals that illustrate a means by which the compounds of theinvention can be prepared.

The compounds of this invention can be prepared by a variety ofprocedures and synthetic routes. Representative procedures and syntheticroutes are shown in, but are not limited to, Schemes 1-17.

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: AcCl for acetyl chloride; DCM fordichloromethane; AIBN for 2,2′-azobis(2-methylpropionitrile); DMA forN,N-dimethylacetamide; DIEA or Hunig's base forN,N-diisopropylethylamine; DMAP for dimethylaminopyridine; DMF forN,N-dimethylformamide; DMSO for dimethylsulfoxide; DMPU for1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; EDCI or EDAC for(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EtOAc forethyl acetate; EtOH for ethanol; Et₂O for diethyl ether; HATU forO-(7-azabenzotriazol-1-yl)-N,N, N′,N′-tetramethyluroniumhexafluoro-phosphate; HOBt for hydroxybenzotriazole hydrate; KOTMS forpotassium trimethylsilanolate; MeOH for methanol; MeCN for acetonitrile;MTBE for methyl t-butyl ether; NMO for N-methylmorpholine N-oxide; TBTUfor O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate;THF for tetrahydrofuran; and, triflate for trifluoromethane sulfonyl

Substituted adamantanes of general formula (3), wherein A¹, A², A³, A⁴,R¹, R², R³, R⁴, D and E are as defined in formula I, may be prepared asin Scheme 1. Substituted adamantamines of general formula (I),purchased, prepared as described herein, or prepared using methodologyknown to those in the art, may be treated with an acylating agents ofgeneral formula (2), wherein Y is chloro, bromo, or fluoro and R³, R⁴, Dand E are defined as in formula I, in the presence of a base such asdiisopropylethylamine to provide amides of general formula (3).Alternatively, acids of general formula (2) wherein Y═OH can be coupledto substituted adamantamines of general formula (I) with reagents suchas EDCT and HOBt to provide amides of general formula (3). In someexamples, A¹, A², A³ and/or A⁴ in amines of formula (I) and D and E inthe reagents of formula (2) may exist as or contain a group furthersubstituted with a protecting group such as a carboxylic acid protectedas the methyl ester. Examples containing a protected functional groupmay be required due to the synthetic schemes and the reactivity of saidgroups and could be later removed to provide the desired compound. Suchprotecting groups can be removed using methodology known to thoseskilled in the art or as described in T. W. Greene, P. G. M. Wuts“Protective Groups in Organic Synthesis” 3^(rd) ed. 1999, Wiley & Sons,Inc.

Substituted adamantane amines of general formula (5), wherein A¹, A²,A³, A⁴ and R² are as defined in formula I, may be prepared as in Scheme2. Substituted adamantane ketones of general formula (4) can bepurchased, prepared as described herein, or prepared using methodologyknown to those skilled in the art. Ketones of general formula (4) can betreated with ammonia or primary amines (R²NH₂) followed by reductionwith reagents such as sodium borohydride or H₂ over Pd/C in a solventlike methanol to provide amines of general formula (5). In someexamples, A¹, A², A³ and/or A⁴ in ketones of formula (4) may be asubstituent with a functional group containing a protecting group suchas a carboxylic acid protected as the methyl ester. Such esters can behydrolyzed and other protecting groups removed here to provide compoundsof general formula (5) or in compounds subsequently prepared from (5)using methodology known to those skilled in the art.

Substituted adamantanes of general formula (7), wherein A², A³ and A⁴are as defined in formula I and G is alkyl, cycloalkyl, arylalkyl, oraryl, as defined in the definition of terms, or G is hydrogen or an acidprotecting group, may be prepared as in Scheme 3. Substitutedadamantanes of general formula (6) can be purchased or prepared usingmethodology known to those in the art. Tertiary alcohols of generalformula (6) can be treated with oleum and formic acid followed by wateror an alcohol GOH to provide polycycles of general formula (7). In someexamples, G in formula (7) may be a protecting group such as methyl.Such ester protecting groups can be removed from polycycles of generalformula (7) or from compounds subsequently prepared from (7).

Substituted adamantanes of general formula (10), wherein A², A³, A⁴, R¹,R², R³, R⁴, D, E, R¹⁸ and R¹⁹ are as defined in formula I, may beprepared as in Scheme 4. Adamantane acids of general formula (8) may beprepared as described herein or using methodology known to those in theart. The acids of general formula (8) may be coupled with amines ofgeneral formula (9) (wherein R¹⁸ and R¹⁹ are defined as in formula I)with reagents such as O-(benzotrialzol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TBTU) to provide amides of general formula (10). Insome examples, R¹⁸ and/or R¹⁹ in amides of formula (10) may be asubstituent with a functional group containing a protecting group, suchas a carboxylic acid protected as the methyl ester. Such esters can behydrolyzed and other protecting groups removed using methodology knownto those skilled in the art.

Acids of general formula (12), wherein R¹⁰¹ is hydrogen, and R³, R⁴, Dand E are as defined in formula (I) can be prepared as shown in Scheme5.

Esters of general formula (11) wherein P is an acid protecting groupsuch as, but not limited to, C₁-C₆ alkyl, unsubstituted or substitutedaryl (for example, phenyl) or unsubstituted or substituted arylalkyl(for example, benzyl), R³ and R⁴ are hydrogen, or one of R³ and R⁴ ishydrogen and the other is as defined in formula (I), can be purchased,prepared as described herein, or prepared using methodologies known tothose skilled in the art. Esters of general formula (11) can bemono-alkylated or bis-alkylated to provide esters of general formula(12) wherein R¹⁰¹ is the acid protecting group, P, as described above.The bis-alkylation can be conducted either sequentially or in a one potreaction.

Mono or bis-alkylation of esters of general formula (11) can be achievedin the presence of a base such as, but not limited to, sodium hydride,and an alkylating agent such as, but not limited to, alkyl halides (forexample, methyl iodide, allyl bromide and the like). The reaction isgenerally performed in a solvent such as, but not limited to, anhydrousN,N-dimethylformamide, at a temperature from about 0° C. to about 23° C.

Removal of the protecting group P can be achieved using methodologiesknown to those skilled in the art or as described in T. W. Greene, P. G.M. Wuts “Protective Groups in Organic Synthesis” 3^(rd) ed. 1999, Wiley& Sons, Inc., to provide compounds of formula (12) wherein R¹⁰¹ ishydrogen. Typically, such transformation can be achieved by stirringwith an acid (for example, hydrochloric acid and the like) or a base(for example, lithium hydroxide, sodium hydroxide and the like) in asolvent such as, but not limited to, dioxane, tetrahydrofuran, ethanol,and mixtures thereof, at ambient temperature or at elevated temperature(typically at about 50° C. to about 70° C.). In cases where P isunsubstituted or substituted arylalkyl (for example, benzyl),hydrogenation can be employed to cleave the acid protecting group.

Synthesis of acids of general formula (15), wherein R¹⁰¹ is hydrogen,R³, R⁴, and D are as defined in formula (I), and G¹ and Z areindependently aryl or heteroaryl, is outlined in Scheme 6.

Esters of formula (13), wherein P is C₁-C₆ alkyl, unsubstituted orsubstituted aryl (for example, phenyl) or unsubstituted or substitutedarylalkyl (for example, benzyl); and Y is Cl, Br, I, or triflate can bepurchased, prepared as described herein, or prepared using methodologiesknown to those skilled in the art. Esters of formula (13) can beconverted to boronic esters of formula (14) when treated with a boronsource like bis(pinacolato)diboron, a catalyst such as1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (H), and a baselike potassium acetate. The conversion is facilitated in a solvent suchas, but not limited to, dimethyl sulfoxide, N,N-dimethylformamide ortoluene, at a temperature of about 80° C. to about 100° C. Boronicesters of general formula (14) may be coupled with reagents of formulaZ—Y, wherein Z is aryl or heteroaryl and Y is Cl, Br, I, or triflate, acatalyst such as 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II), and a base like sodium carbonate, to provide compounds of formula(15) wherein R¹⁰¹ is an acid protecting group, P. The reaction can beperformed in a solvent system like N,N-dimethylformamide and water at atemperature of about 80° C. to 90° C.

Alternatively, compounds of formula (13) wherein Y is Cl, Br, I, ortriflate can be treated with a boronic acid or ester of formula (13A) orZ—B(OR¹⁰²)₂, wherein R¹⁰² is hydrogen or alkyl, in the presence of acatalyst, such as but not limited to, bis(triphenylphospine)palladium(II) chloride or dichlorobis(tri-o-tolylphosphine)palladium (II), and abase such as triethylamine or sodium carbonate, to provide compounds offormula (15) wherein R¹⁰¹ is an acid protecting group, P. The reactioncan be effected by heating at a temperature from about 50° C. to about180° C. in solvents such as isopropanol, ethanol, dimethoxyethane, wateror dioxane.

Conversion of compounds of formula (15) wherein R¹⁰¹ is an acidprotecting group, P, to compounds of formula (15) wherein R¹⁰¹ ishydrogen can be prepared using reaction conditions as described inScheme 5.

Acids of general formula (19), wherein R¹⁰¹ is hydrogen, R³ is asdefined in formula (I) and A is a substituent of heterocycle as definedin the definition of terms, can be prepared from malonic acid di-esterof formula (16) wherein P is C₁-C₆ alkyl or benzyl as shown in Scheme 7.

Malonic acid di-esters of general formula (16) wherein P is an acidprotecting group such as C₁-C₆ alkyl, unsubstituted or substituted aryl(for example, phenyl) or unsubstituted or substituted arylalkyl (forexample, benzyl), can be purchased or prepared using methodologies knownto those skilled in the art. Malonic acid di-esters of general formula(16) can be treated with one molar equivalent of allyl bromide or4-bromo-1-butene, using mono alkylation conditions for the conversion of(11) to (12) in Scheme 5, to provide compounds of formula (17).Ozonolysis of the terminal olefin of di-ester (17) may be achieved in asolvent system like dichloromethane and methanol at a low temperature ofabout −78° C., by bubbling ozone through the solution, followed bypurging the solution with nitrogen gas, and reduction of theintermediate ozonide with dimethyl sulfide to provide aldehyde di-estersof the general formula (18). Treatment of aldehyde di-ester (18) with aprimary amine of formula A-NH₂, wherein A is a substituent ofheterocycle as defined in the definition of terms, a reducing agent likeresin bound MP-triacetoxy borohydride, and in a solvent liketetrahydrofuran at a temperature around 23° C., provides esters ofgeneral formula (19) wherein R¹⁰¹ is an acid protecting group, P.Removal of P using reaction conditions as outlined in Scheme 5 converts(19) wherein R¹⁰¹ is an acid protecting group, P, to compounds offormula (19) wherein R¹⁰¹ is hydrogen.

Scheme 8 outlines the synthesis of esters of general formula (23),wherein P¹ is an acid protecting group such as, but not limited to,C₁-C₆ alkyl, and X¹ and X² are substituents of heteoraryl as defined inthe definition of terms, from thiazoles of formula (20).

Thiazoles of formula (20) can be purchased or prepared usingmethodologies known to those skilled in the art. Thiazoles of formula(20) may be alkylated by in situ activation with a chloroformate suchas, but not limited to, ethyl chloroformate, followed by treatment of anucleophile such as lithio diethylmalonate (prepared from a malonic aciddi-ester in a solution such as tetrahydrofuran with a base such aslithium bis(trimethylsilyl)amide), to afford compounds of formula (21)wherein P¹ and P² are C₁-C₆ alkyl. The former can be conducted in asolvent such as, but not limited to, tetrahydrofuran, at a temperaturearound 0° C. Treatment with the nucleophile can be effected in a solventsuch as tetrahydrofuran and at a temperature around 23° C. The lithiodiethylmalonate may be formed in a solvent such as tetrahydrofuran. TheN-protected malonic acid di-ester adduct of general formula (21) may beoxidized with an agent such as tetrachloro-1,2-benzoquinone in a solventsuch as dichloromethane at a temperature around 0° C. to afford thedi-ester of general formula (22). Mono-decarboxylation of di-ester (22)may be achieved by heating in a solvent system such as water anddimethyl sulfoxide with a salt such as sodium chloride at a temperaturenear 180° C. to provide esters of general formula (23).

Acids of formula (27) wherein R¹⁰¹ is hydrogen, P³ is —C(O)OCH₂C₆H₅, andR³ is as defined in formula (I) can be prepared from compounds offormula (24) where P is an acid protecting group such as, C₁-C₆ alkyl,unsubstituted or substituted aryl (for example, phenyl) or unsubstitutedor substituted arylalkyl (for example, benzyl), as shown in Scheme 9.

Compounds of formula (24) can be purchased or prepared usingmethodologies known to those skilled in the art. Treatment of compoundsof formula (24) with benzyl chloroformate and a base such as, but notlimited to, sodium bicarbonate in water, provides compounds of formula(25) wherein P³ is —C(O)OCH₂C₆H₅. Mono alkylation of compounds offormula (25) with halides of formula R³—X³ wherein X³ is Cl, Br or I,using reaction conditions as described in Scheme 5 provides compounds offormula (26).

Conversion of compounds of formula (26) to compounds of formula (27)wherein R¹⁰¹ is hydrogen can be achieved using reaction conditions asdescribed in Scheme 5 for removal of a protecting group, P.

Compounds of general formula (29), wherein R³, R⁴, R²⁷, R²⁸, R²⁹, R³⁰,and R³¹ are as defined in formula I; G² is —N(R³¹)—, —O— or —S—; Z¹ isaryl or heteroaryl; R¹⁰¹ is hydrogen or is an acid protecting group, P,such as, but not limited to, C₁-C₆ alkyl, unsubstituted or unsubstitutedaryl (for example, phenyl) or unsubstituted or substituted arylalkyl(for example benzyl), can be prepared as shown in Scheme 10.

Compounds of formula (28) can be purchased, prepared as describedherein, or prepared using methodologies known to those skilled in theart. Compounds of formula (28) wherein P is an acid protecting group canbe reacted with compounds of formula Z¹—Y, wherein Y is Cl, Br, I, ortriflate such as 6-chloronicotinonitrile, with a base such as sodiumhydride, and in an anhydrous solvent system such as tetrahydrofuran and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) at atemperature ranging from 0° C. to 23° C. to provide esters of generalformula (29), wherein R¹⁰¹ is a protecting group, P.

Conversion of compounds of formula (29) wherein R¹⁰¹ is P to compoundsof formula (29) wherein R¹⁰¹ is hydrogen can be achieved using reactionconditions as described in Scheme 5 for removal of a protecting group,P.

Compounds of general formula (31), wherein R³ and R⁴ are as defined informula (I), G³ is aryl or heteroaryl, and R¹⁰³ is hydrogen, potassium,sodium, lithium, or C₁-C₆ alkyl, can be prepared as shown in Scheme 11.

Compounds of formula G³-Y wherein G³ is aryl or heteroaryl and Y is Cl,Br, I or triflate can be purchased or prepared using methodologies knownto those skilled in the art, as well as, alkyl trimethylsilyl keteneacetals of formula (30) wherein R¹⁰³ is C₁-C₆ alkyl. Compounds offormula G³-Y such as, but not limited to,2-chloro-5-(trifluoro-methyl)pyridine can be reacted with an alkyltrimethylsilyl ketene acetal of formula (30) wherein R¹⁰³ is C₁-C₆ alkylsuch as, but not limited to, methyl or ethyl; a salt such as zincfluoride; a catalyst such as tris(dibenzylideneacetone)dipalladium (0);a ligand such as tri-t-butylphosphine; and, in a solvent such asN,N-dimethylformamide at a temperature of about 90° C. to provide estersof general formula (31) wherein R¹⁰³ is C₁-C₆ alkyl.

Numerous methodologies for the conversion of compounds of formula (31)wherein R¹⁰³ is C₁-C₆ alkyl to compounds of formula (31) wherein R¹⁰³ ishydrogen are described in “Protective Groups in Organic Synthesis”3^(rd) edition, 1999, Wiley & Sons, Inc. Additionally, one can obtain asalt of compounds of formula (31) where R¹⁰¹ is potassium, sodium, orlithium by stirring compounds of formula (31) wherein R¹⁰³ is C₁-C₆alkyl with a base such as, but not limited to, potassiumtrimethylsilanolate in a solvent such as, but not limited to,tetrahydrofuran, at ambient temperature.

Compounds of formula (32) wherein Y is Cl, Br, I or triflate, G⁴ is arylor heteroaryl as defined in the definition of terms, and A¹, A², A³, A⁴,R², R³, R⁴ and D are as defined in formula (I) can be prepared asdescribed herein or prepared using methodologies known to those skilledin the art. Conversion of compounds of formula (32) to compounds offormula (33), depicted in Scheme 12, wherein Z² is aryl or heteroarylcan be achieved using the series of reaction conditions as described inScheme 6 for the transformation of (13) to (15).

Adamantanes of general formula (36), wherein A¹, A², A³, A⁴, R¹, R², R³,R⁴ and D are as defined in formula (I), and G⁵ and Z³ are independentlyeither aryl or heteroaryl as defined in the definition of terms, can beprepared as shown in Scheme 13.

Adamantanes of general formula (34) wherein Y is Cl, Br or I, can beprepared as described herein or prepared using methodologies known tothose skilled in the art. Olefins of general formula (35) wherein Z³ iseither aryl or heteroaryl can be purchased or prepared usingmethodologies known to those skilled in the art. Adamantanes of generalformula (34) can be reacted with olefins of general formula (35), suchas, but not limited to, 4-vinylpyridine; a catalyst such as, but notlimited to, bis(triphenylphosphine)palladium (II) dichloride; a basesuch as, but not limited to, triethylamine; and, in a solvent systemsuch as N,N-dimethylformamide at a temperature of near 150° C. toprovide adamantanes of general formula (36).

Substituted adamantanes of general formula (38), wherein A¹, A², A³, A⁴,R¹, R², R³, R⁴, and D are as defined in formula (I); G⁶ is aryl orheteroaryl; and, Q is alkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, or cycloalkylalkyl, can be prepared as shown in Scheme 14.

Substituted adamantanes of general formula (37) can be prepared asdescribed herein or prepared using methodologies known to those skilledin the art. Substituted adamantanes of general formula (37) can bealkylated with alkylating agents Q-Y, wherein Q is alkyl, arylalkyl,heteroarylalkyl, heterocycle alkyl, or cycloalkylalkyl and Y is aleaving group like I, Br, Cl, or triflate, in the presence of a baselike potassium carbonate and in a solvent like N,N-dimethylformamide toyield substituted adamantanes of general formula (38).

Substituted adamantanes of general formula (40), wherein A¹, A², A³, A⁴,R², R³, R⁴, and D are as defined in formula I; G⁷ is aryl or heteroaryl;and, R^(k) and R^(m) are independently hydrogen, alkyl, orheterocyclealkyl, or R^(k) and R^(m) together with the nitrogen to whichthey are attached form a heterocycle ring, can be prepared as shown inScheme 15.

Substituted adamantanes of general formula (39), wherein Y is F, Cl, Br,or I, can be prepared as described herein or prepared usingmethodologies known to those skilled in the art. Substituted adamantanesof general formula (39) can be condensed with amines of general formulaR^(k)R^(m)NH, to provide compounds of formula (40). The reaction can beconducted neat in a microwave synthesizer at a temperature near 150° C.for a period of about 40 minutes.

Substituted adamantanes of general formula (43), wherein A¹, A², A³, A⁴,R¹, R², R³, R⁴, and D are as defined in formula I; G⁸ is aryl orheteroaryl as defined in the definition of terms; Q¹ is C₁-C₃ alkyl;and, R^(q) and R^(r) are independently hydrogen, alkyl, orheterocyclealkyl, or R^(q) and R^(r) together with the nitrogen to whichthey are attached form a heterocycle ring, can be prepared as shown inScheme 16.

Substituted adamantanes of general formula (41) can be prepared asdescribed herein or prepared using methodologies known to those skilledin the art. Substituted adamantanes of general formula (41) can behalogenated with a reagent like N-halosuccinimde (for example,N-chlorosuccinimide and the like) in the presence of a radical initiatorlike AIBN and in a solvent like carbon tetrachloride at a temperaturenear 80° C. to yield substituted adamantanes of general formula (42),wherein Y is Cl, Br, or I. Substituted adamantanes of general formula(42) when treated with amines of general formula R^(q)R^(r)NH in asolvent like dichloromethane at a temperature between 23° C. and 40° C.provide substituted adamantanes of general formula (43).

Substituted adamantanes of general formula (50), wherein A², A³, A⁴, R²,R⁵ and R⁶ are as defined in formula I, can be prepared as shown inScheme 17.

Substituted adamantanes of general formula (6) can be purchased orprepared using methodology known to those in the art. Substitutedadamantanes of general formula (6) can be brominated with a reagent likehydrobromic acid in a solvent like water to provide bromides of generalformula (44). Adamantanes of general formula (44) when treated withethylene glycol and a catalytic amount of an acid like p-toluenesulfonicacid in a solvent like benzene provide adamantanes of general formula(45). Bromides of general formula (45) can be (a) treated with Riekezinc in a solvent like tetrahydrofuran; and (b) followed by treatmentwith reagent (46) (prepared as described in Han, Z.; Krishnamurthy, D.;Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002, 124,7880-7881) in a solvent like tetrahydrofuran to provide adamantanes ofgeneral formula (47). Adamantanes of general formula (47) may be treatedwith lithium amide of formula LiNHR⁵R⁶ (prepared in situ by reactingammonia with lithium or amines of formula R⁵R⁶NH wherein R⁵ and R⁶ areother than hydrogen, with t-butyl lithium) in a solvent liketetrahydrofuran. The resulting sulfinamides can be oxidized with areagent like osmium tetroxide with a catalyst oxidant like NMO in asolvent like tetrahydrofuran to provide sulfonamides of general formula(48). Adamantanes of general formula (48) can be deketalized withreagents like hydrochloric acid in a solvent mixture like water andtetrahydrofuran to provide ketones of formula (49). Ketones of formula(49) can be treated with amines of formula R²NH₂ followed by reductionwith reducing reagents such as, but not limited to, sodium borohydrideor hydrogen over Pd/C in a solvent like methanol to provide amines ofgeneral formula (50). In some examples, A², A³, A⁴, R², R⁵ and R⁶ inamines of formula (50) may be a substituent with a functional groupcontaining a protecting group such as a carboxylic acid protected as themethyl ester. Such esters can be hydrolyzed and other protecting groupsremoved here or in compounds subsequently prepared from (50) usingmethodology known to those skilled in the art.

It is understood that the schemes described herein are for illustrativepurposes and that routine experimentation, including appropriatemanipulation of the sequence of the synthetic route, protection of anychemical functionality that are not compatible with the reactionconditions and deprotection are included in the scope of the invention.Protection and Deprotection of carboxylic acids and amines are known toone skilled in the art and references can be found in “Protective Groupsin Organic Synthesis”, T. W. Greene, P. G. M. Wuts, 3rd edition, 1999,Wiley & Sons, Inc.

The compounds and processes of the present invention will be betterunderstood by reference to the following Examples, which are intended asan illustration of and not a limitation upon the scope of the invention.Further, all citations herein are incorporated by reference.

Compounds of the invention were named by ACD/ChemSketch version 5.01(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or were given names consistent with ACD nomenclature. Adamantane ringsystem isomers were named according to common conventions. Twosubstituents around a single ring within an adamantane ring system aredesignated as being of Z or E relative configuation (for examples see C.D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 63:2758-2760, 1998).

Example 1E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylicacid Example 1A 4-oxo-adamantane-1-carboxylic acid

A 5 L 4-neck flask equipped with N₂ inlet/bubbler with H₂O trap,overhead stirring, and an addition funnel was charged with 30% oleum(˜10.5 volumes, 2.2 L, 8×500 g bottles+100 mL), and heated to 50° C.under a slight N₂ flow. 5-Hydroxy-2-adamantanone (220 g, 81 wt % purity,1.07 mol) was dissolved in 5 volumes HCO₂H (˜98%, 1.10 L) and addeddrop-wise to the warm oleum solution over 5 hours. The addition rate wasadjusted to maintain the internal temperature between 70-90° C. Afterstirring an additional 2 hours at 70° C. The reaction solution wascooled to 10° C. in an ice bath. 20 volumes of 10% NaCl aq (4 L) werecooled to <10° C., the crude reaction mixture was quenched into thebrine solution in batches, maintaining an internal temperature <70° C.The quenched reaction solution was combined with a second identicalreaction mixture for isolation. The combined product solutions wereextracted 3×5 volumes with CH₂Cl₂ (3×2.2 L) and the combined CH₂Cl₂layers were then washed 1×2 volumes with 10% NaCl (1 L). The CH₂Cl₂solution was then extracted 3×5 volumes with 10% Na₂CO₃ (3×2.2 L). Thecombined Na₂CO₃ extracts were washed with 1×2 volumes with CH₂Cl₂ (1 L).The Na₂CO₃ layer was then adjusted to pH 1-2 with concentrated HCl(−2volumes, product precipitates out of solution). The acidic solution wasthen extracted 3×5 volumes with CH₂Cl₂ (3×2.2 L), and the organic layerwas washed 1×2 volumes with 10% NaCl. The organic solution was thendried over Na₂SO₄, filtered, concentrated to ˜¼ volume, then chasedistilled with 2 volumes EtOAc (1 L). Nucleation occurred during thisdistillation. The suspension was then chase distilled 2×5 volumes (2×2L) with heptane and cooled to room temperature. The suspension was thenfiltered, and the liquors were recirculated 2× to wash the wet cake. Theresultant material was dried overnight at 50° C., 20 mm Hg to afford thetitle compound.

Example 1B E- and Z-4-amino-adamantane-1-carboxylic acid

To 1.0 g (10 wt %) of 5% Pd/C is added 10.0 g of the product fromExample 1A followed by 200 mL (20 volumes) of 7M NH₃ in MeOH. Thereaction mixture is stirred under an atmosphere of H₂ at RT for 16-24hours. 200 mL of water is added and the catalyst is removed byfiltration. The catalyst is washed with MeOH. Solvent is removed bydistillation at a bath temperature of 35° C. until solvent stops comingover. Approximately 150 mL of a slurry remains. 300 ml, of MeCN is addedto the slurry, which is then stirred for three hours at RT. The slurryis filtered and washed once with 100 mL MeCN. The wet cake is dried at50° C. and 20 mm Hg under N₂ to afford the title compound with a13.1:1.0 E:Z ratio by ¹H-NMR (D₂O).

Example 1C E-4-amino-adamantane-1-carboxylic acid methyl esterhydrochloride

Methanol (10 volumes, 85 mL) was cooled to 0° C. AcCl was added dropwise(5.0 equiv., 15.5 mL), and the solution was warmed to ambienttemperature for 15-20 minutes. The product from Example 1B (8.53 g, 43.7mmol, 1.0 equiv.) was added and the reaction solution was heated to 45°C. for 16 hours (overnight). Consumption of the starting aminoacid wasmonitored by LC/MS (APCI). The reaction solution was then cooled to roomtemperature, 10 volumes McCN (85 mL) was added, distilled to ˜¼ volume(heterogeneous), and chase distilled 2×10 volumes with MeCN (2×85 mL).The resulting suspension was cooled to room temperature, filtered, andthe filtrate was recirculated twice to wash the wet cake. The productwas dried at 50° C., 20 mm Hg overnight to afford the title compound.

Example 1DE-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylicacid

Step A

A solution of the product from Example 1C (50 mg, 0.20 mmol),1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid (39 mg, 0.19 mmol), andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (65 mg, 0.20 mmol) in N,N-dimethylacetamide (DMA) (2 mL) and DIEA(80 μL, 0.46 mmol) was stirred for 16 hours at 23° C. The reactionmixture was analyzed by LC/MS and determined to be near completion. Thereaction mixture was concentrated under reduced pressure. The residuewas taken up in methylene chloride and washed with 1 N HCl (2×),saturated NaHCO₃ (2×), water, and brine before drying over Na₂SO₄,filtering, and concentrating under reduced pressure. The resultant solidwas triturated with ethyl acetate, dried under reduced pressure toprovide the methyl ester of the titled compound.

Step B

The methyl ester of the titled compound obtained from step A (50 mg,0.12 mmol) was dissolved in 3 N HCl (1 mL), dioxane (0.25 mL), and 4 NHCl (1 mL). The homogenous acid solution was heated to 60° C. for 24hours, was cooled to 23° C., and was then concentrated under reducedpressure to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ12.02 (s, 1H), 7.40 (m, 4H), 6.87 (d, J=6.6 Hz, 1H), 3.68 (m, 1H), 2.71(m, 2H), 2.36 (m, 2H), 1.75 (m, 13H), 1.34 (m, 2H); MS (ESI+) m/z 389(M+H)⁺.

Example 2E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic acid

Step A

The methyl ester of the titled compound was prepared according to themethod of step A of Example 1D substituting1-phenyl-1-cyclopropanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and the crude methylester was purified by chromatography on flash silica gel with an eluantgradient of 20-40% ethyl acetate/hexanes.

Step B

The methyl ester obtained from step A (47 mg, 0.13 mmol) was dissolvedin 3 N HCl (1 mL), dioxane (0.25 mL), and 4 N HCl (1 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound. NMR (300 MHz, DMSO-d₆) δ12.05 (s, 1H), 7.43 (m, 4H), 7.36 (m, 1H), 5.80 (d, J=7.8 Hz, 1H), 3.72(m, 1H), 1.79 (m, 6H), 1.71 (m, 3H), 1.40 (m, 1H), 1.35 (m, 3H), 1.20(m, 2H), 1.02 (m, 2H); MS (ESI+) m/z 341 (M+H)⁺.

Example 3 E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylicacid

Step A

The methyl ester of the titled compound was prepared according to themethod of step A of Example 1D substituting 2-methyl-2-phenyl propionicacid for 1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and the crudemethyl ester was purified by chromatography on flash silica gel with aneluant gradient of 20-40% ethyl acetate/hexanes.

Step B

The methyl ester obtained from step A (49 mg, 0.14 mmol) was dissolvedin 3 N HCl (1 mL) and dioxane (0.25 mL), heated to 60° C. for 24 hours,was cooled to 23° C., and was then concentrated under reduced pressureto provide the title compound. NMR (300 MHz, DMSO-d₆) δ 12.04 (s, 1H),7.34 (m, 4H), 7.24 (m, 1H), 6.26 (d, J=6.9 Hz, 1H), 3.74 (m, 1H), 1.87(m, 2H), 1.81 (m, 4H), 1.74 (m, 3H), 1.55 (m, 2H), 1.49 (s, 6H), 1.35(m, 2H); MS (ESI+) m/z 343 (M+H)⁺.

Example 4E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylicacid amide

A solution of the product from step B of Example 1D (24 mg, 0.062 mmol)in DCM (2 mL) was treated with HOBt (12 mg, 0.090 mmol) and EDCI (20 mg,0.10 mmol) and stirred at room temperature for 1 hour. Excess of aqueous(35%) ammonia (1 mL) was added and the reaction was stirred for 16hours. The layers were separated and the aqueous extracted twice morewith methylene chloride (2×2 mL). The combined organic extracts weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified bypreparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 umparticle size) using a gradient of 10% to 100% acetonitrile:aqueousammonium acetate (10 mM) over 8 minutes (10 minute run time) at a flowrate of 40 mL/minute on reverse phase HPLC to afford the title compoundupon concentration under reduced pressure. ¹H NMR (300 MHz, DMSO-d₆) δ7.40 (m, 4H), 6.94 (s, 1H), 6.84 (d, J=6.6 Hz, 1H), 6.68 (s, 1H), 3.69(m, 1H), 2.71 (m, 2H), 2.35 (m, 2H), 1.76 (m, 13H), 1.32 (m, 2H); MS(ESI+) m/z 388 (M+H)⁺.

Example 5E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic acidamide

The title compound was prepared according to the method of Example 4substituting the product from step B of Example 2 for the product fromstep B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 7.42 (m, 4H), 7.36 (m,1H), 6.94 (s, 1H), 6.68 (s, 1H), 6.78 (d, J=7.8 Hz, 1H), 3.73 (m, 1H),1.75 (m, 7H), 1.65 (m, 2H), 1.35 (m, 4H), 1.18 (m, 2H), 1.02 (m, 2H); MS(ESI+) m/z 340 (M+H)⁺.

Example 6 E-4-(2-Methyl-2-phenylpropionylamino)-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method of Example 4substituting the product from step B of Example 3 for the product fromstep B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ 7.35 (m, 4H), 7.25 (m,1H), 6.96 (s, 1H), 6.69 (s, 1H), 6.23 (d, J=7.2 Hz, 1H), 3.74 (m, 1H),1.85 (m, 2H), 1.75 (m, 5H), 1.69 (m, 2H), 1.53 (m, 2H), 1.49 (s, 6H),1.32 (m, 2H); MS (ESI+) m/z 342 (M+H)⁺.

Example 7 N-2-adamantyl-2-methyl-2-phenylpropanamide

A solution of 2-adamantanamine hydrochloride (38 mg, 0.20 mmol),2-phenylisobutyric acid (30 mg, 0.19 mmol), andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (65 mg, 0.20 mmol) in N,N-dimethylacetamide (DMA) (2 mL) and DIEA(80 μL, 0.46 mmol) was stirred for 16 hours at 23° C. The reactionmixture was analyzed by LC/MS and determined to be near completion. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparativeHPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size)using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate(10 mM) over 8 minutes (10 minute run time) at a flow rate of 40mL/minute on reverse phase HPLC to afford the title compound uponconcentration under reduced pressure. ¹H NMR (300 MHz, DMSO-d₆) δ 7.35(m, 4H), 7.24 (m, 1H), 6.16 (d, J=6.9 Hz, 1H), 3.78 (m, 1H), 1.74 (m,7H), 1.64 (m, 3H), 1.55 (m, 2H), 1.48 (s, 6H), 1.41 (m, 2H); MS (DCI+)m/z 298 (M+H)⁺.

Example 8 N-2-adamantyl-1-phenylcyclopropanecarboxamide

The titled compound was prepared according to the method of Example 7substituting

1-phenyl cyclopropanecarboxylic acid for 2-phenylisobutyric acid. ¹H NMR(300 MHz, DMSO-d₆) δ 7.43 (m, 4H), 7.37 (m, 1H), 5.77 (d, J=7.8 Hz, 1H),3.76 (m, 1H), 1.68 (m, 10H), 1.42 (m, 2H), 1.35 (m, 2H), 1.21 (m, 2H),1.01 (m, 2H); MS (DCI+) m/z 296 (M+H)⁺.

Example 9E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxamideExample 9AE-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(4-chlorophenyl)-1-cyclohexanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (47 mg, 0.11 mmol) was dissolvedin 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 9BE-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4 substituting the product of step B of Example 9A for theproduct of step B of Example 1D, and with the exception that the crudetitle compound was purified by normal phase flash chromatography withMeOH/DCM (5:95) as eluant. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.36-7.42 (m,4H), 6.95-6.96 (bs, 1H), 6.69-6.70 (bs, 1H), 6.57 (d, J=6.56 Hz, 1H),3.72-3.76 (m, 1H), 2.36-2.44 (m, 2H), 1.84-1.86 (m, 2H), 1.73-1.82 (m,5H), 1.64-1.73 (m, 6H), 1.49-1.56 (m, 3H), 1.36-1.51 (m, 2H), 1.32-1.36(m, 2H), 1.23-1.30 (m, 1H); MS (ESI+) m/z 415 (M+H)⁺.

Example 10E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamideExample 10AE-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(4-chlorophenyl)-1-cyclopropanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (51 mg, 0.13 mmol) was dissolvedin 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 10BE-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 10A for theproduct of step B of Example 1D and with the exception that titlecompound was purified by normal phase flash chromatography with MeOH/DCM(5:95) as eluant. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.43-7.48 (m, 4H),6.95-6.97 (bs, 1H), 6.69-6.70 (bs, 1H), 5.98 (d, J=7.30 Hz, 1H),3.71-3.76 (m, 1H), 1.79-1.82 (m, 2H), 1.73-1.78 (m, 5H), 1.67-1.69 (m,2H), 1.29-1.41 (m, 6H), 0.99-1.03 (m, 2H); MS (ESI+) m/z 373 (M+H)⁺.

Example 11E-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamideExample 11AE-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (30 mg, 0.072 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 11BE-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 11A for theproduct of step B of Example 1D, and with the exception that titlecompound was purified by normal phase flash chromatography with MeOH/DCM(5:95) as eluant. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.35-7.41 (m, 4H),6.94-6.96 (bs, 1H), 6.68-6.70 (bs, 1H), 6.58 (d, J=6.59 Hz, 1H),3.66-3.70 (m, 1H), 2.51-2.60 (m, 2H), 1.77-1.86 (m, 5H), 1.73-1.77 (m,4H), 1.68-1.69 (m, 2H), 1.58-1.66 (m, 6H), 1.30-1.34 (m, 2H); MS (ESI+)m/z 401 (M+H)⁺.

Example 12E-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamideExample 12AE-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting2-methyl-2-(4-chlorophenyl) propionic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 m L/min.

Step B

The methyl ester obtained from step A (50 mg, 0.13 mmol) was dissolvedin 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 12BE-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 12A for theproduct of step B of Example 1D, and with the exception that titlecompound was purified by normal phase flash chromatography with MeOH/DCM(5:95) as eluant. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.34-7.40 (m, 4H),6.95-6.97 (bs, 1H), 6.69-6.71 (bs, 1H), 6.44 (d, J=6.72 Hz, 1H),3.73-3.77 (m, 1H), 1.86-1.89 (m, 2H), 1.69-1.81 (m, 5H), 1.67-1.73 (m,2H), 1.61-1.66 (m, 2H), 1.47 (s, 6H), 1.32-1.36 (m, 2H); MS (ESI+) m/z375 (M+H)⁺.

Example 13E-4-{[(1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxamideExample 13AE-4-{[(1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxylic acid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-phenyl-1-cyclopentanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (20 mg, 0.052 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 13BE-4-{[(1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 13A for theproduct of step B of Example 1D, and with the exception that titlecompound was purified by normal phase flash chromatography with MeOH/DCM(5:95) as eluant. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.38-7.40 (m, 2H),7.30-7.34 (m, 2H), 7.20-7.24 (m, 1H), 6.93-6.95 (bs, 1H), 6.68-6.69 (bs,1H), 6.38 (d, J=6.80 Hz, 1H), 3.65-3.69 (m, 1H), 2.51-2.58 (m, 2H),1.78-1.90 (m, 4H), 1.71-1.78 (m, 5H), 1.65-1.69 (m, 2H), 1.60-1.64 (m,4H), 1.51-1.56 (m, 2H), 1.28-1.32 (m, 2H); MS (ESI+) m/z 367 (M+H)⁺.

Example 14E-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamideExample 14AE-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(3-fluorophenyl)-1-cyclopentanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (41 mg, 0.10 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 14BE-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 14A for theproduct of step B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm7.31-7.40 (m, 1H), 7.18-7.24 (m, 2H), 7.01-7.09 (m, 1H), 6.93-6.96 (bs,1H), 6.68-6.70 (bs, 1H), 6.60 (d, J=6.55 Hz, 1H), 3.64-3.71 (m, 1H),2.48-2.66 (m, 2H), 1.71-1.88 (m, 9H), 1.58-1.71 (m, 8H), 1.29-1.35 (m,2H); MS (ESI+) m/z 385 (M+H)⁺.

Example 15E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamideExample 15AE-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(2-chloro-4-fluorophenyl)-1-cyclopentanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (66 mg, 0.15 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 15BE-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 15A for theproduct of step B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.61(dd, J=8.86, 6.18 Hz, 1H), 7.43 (dd, J=8.66, 2.77 Hz, 1H), 7.24 (ddd,J=8.81, 8.11, 2.80 Hz, 1H), 6.94-6.96 (m, 1H), 6.68-6.71 (bs, 1H), 5.84(d, J=6.96 Hz, 1H), 3.69-3.77 (m, 1H), 2.35-2.51 (m, 2H), 1.92-2.08 (m,2H), 1.53-1.89 (m, 13H), 1.28-1.45 (m, 4H); MS (ESI+) m/z 419 (M+H)⁺.

Example 16E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamideExample 16AE-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(4-fluorophenyl)-1-cyclopentanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (58 mg, 0.15 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 16BE-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 16A for theproduct of step B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm7.37-7.45 (m, 2H), 7.10-7.17 (m, 2H), 6.93-6.96 (bs, 1H), 6.67-6.70 (bs,1H), 6.50 (d, J=6.65 Hz, 1H), 3.64-3.70 (m, 1H), 2.51-2.61 (m, 2H),1.54-1.86 (m, 17H), 1.27-1.37 (m, 2H); MS (ESI+) m/z 385 (M+H)⁺.

Example 17E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamideExample 17AE-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(2-fluorophenyl)-1-cyclopentanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (56 mg, 0.14 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 17BE-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 17A for theproduct of step B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.49(td, J=7.94, 1.80 Hz, 1H), 7.29-7.37 (m, 1H), 7.11-7.24 (m, 2H),6.94-6.96 (bs, 1H), 6.68-6.70 (bs, 1H), 6.02 (d, J=6.93 Hz, 1H),3.67-3.74 (m, 1H), 2.34-2.53 (m, 2H), 1.85-2.01 (m, 2H), 1.57-1.86 (m,13H), 1.28-1.43 (m, 4H); MS (ESI+) m/z 385 (M+H)⁺.

Example 18E-4-{[1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide Example18A E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-methyl-1-cyclohexanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (33 mg, 0.10 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 18BE-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 18A for theproduct of step B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm6.96-6.99 (bs, 1H), 6.66-6.72 (m, 2H), 3.74-3.80 (m, 1H), 1.82-2.08 (m,7H), 1.79-1.82 (m, 4H), 1.72-1.75 (m, 2H), 1.12-1.55 (m, 10H), 1.07 (s,3H); MS (ESI+) m/z 319 (M+H)⁺.

Example 19E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamideExample 19AE-4-({[1-(2,4-dichlorophenyl)cyclopronyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(2,4-dichlorophenyl)-1-cyclopropanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (47 mg, 0.11 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 19BE-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 19A for theproduct of step B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.73(d, J=2.10 Hz, 1H), 7.56 (d, J=8.25 Hz, 1H), 7.49 (dd, J=8.27, 2.12 Hz,1H), 6.94-6.97 (bs, 1H), 6.68-6.71 (bs, 1H), 5.66 (d, J=7.12 Hz, 1H),3.70-3.77 (m, 1H), 1.80-1.84 (m, 2H), 1.71-1.78 (m, 5H), 1.68 (d, J=3.09Hz, 2H), 1.43-1.53 (m, 2H), 1.27-1.42 (m, 4H), 1.02-1.12 (m, 2H); MS(ESI+) m/z 407 (M+H)⁺.

Example 20E-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamideExample 20AE-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(4-methoxyphenyl)-1-cyclopropanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (43 mg, 0.11 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 20BE-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 20A for theproduct of step B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm7.34-7.38 (m, 2H), 6.95-7.00 (m, 3H), 6.68-6.71 (bs, 1H), 5.78 (d,J=7.66 Hz, 1H), 3.76 (s, 3H), 3.69-3.75 (m, 1H), 1.72-1.77 (m, 7H),1.66-1.69 (m, 2H), 1.27-1.43 (m, 4H), 1.17-1.24 (m, 2H), 0.93-1.03 (m,2H); MS (ESI+) m/z 369 (M+H)⁺.

Example 21E-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamideExample 21AE-4-{[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylicacid

Step A

The methyl ester of the title compound was prepared according to themethod as described in step A of Example 1D, substituting1-(4-methylphenyl)-1-cyclopropanecarboxylic acid for1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid and with the exceptionsthat the methyl ester was purified by reverse phase chromatography. Uponwork up, the residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) andpurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 10% to 100%acetonitrile:aqueous ammonium acetate (10 mM) over 8 min (10 min runtime) at a flow rate of 40 mL/min.

Step B

The methyl ester obtained from step A (39 mg, 0.11 mmol) was dissolvedin 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1 mL), heated to 60°C. for 24 hours, was cooled to 23° C., and was then concentrated underreduced pressure to provide the title compound.

Example 21BE-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide

The title compound was prepared according to the method as described inExample 4, substituting the product of step B of Example 21A for theproduct of step B of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm7.30-7.34 (m, 2H), 7.20-7.25 (m, 2H), 6.94-6.97 (bs, 1H), 6.68-6.70 (bs,1H), 5.80 (d, J=7.62 Hz, 1H), 3.69-3.76 (m, 1H), 2.31 (s, 3H), 1.71-1.81(m, 7H), 1.66-1.68 (m, 2H), 1.31-1.39 (m, 4H), 1.17-1.23 (m, 2H),0.96-0.99 (m, 2H); MS (ESI+) m/z 353 (M+H)⁺.

Example 22E-4-{[2-methyl-2-(4-pyridin-4-ylphenyl)propanoyl]amino}adamantane-1-carboxamideExample 22A Ethyl 2-(4-bromophenyl)-2-methylpropanoate

A 60% suspension of sodium hydride in mineral oil (3.3 g, 82.3 mmoles)was added to N,N-dimethylformamide (60.0 ml) under a nitrogen atmosphereand the mixture was cooled to about −10° C. Iodomethane (5.1 ml, 82.3mmoles) and subsequently ethyl 4-bromophenylacetate (5.0 g, 20.6 mmoles)were added over a period of about 30 min and the reaction mixture wasthen stirred for about 16 hours while being allowed to warm to roomtemperature. This suspension was then poured onto a mixture of ice and2N hydrochloric acid (30.0 ml) and was extracted four times with ethylacetate. The combined organic extracts were washed with water and brine,dried over MgSO₄ and filtered. The filtrate was concentrated underreduced pressure and the crude product was purified by flash columnchromatography on silica gel using hexanes/ethyl acetate (2:1) as themobile phase to provide the title compound.

Example 22B 2-(4-bromophenyl)-2-methylpronanoic acid

To a solution of the product of Example 22A (3.7 g, 13.6 mmoles) intetrahydrofuran (110.0 ml) and methanol (37.0 ml) was added 2 N sodiumhydroxide (19.0 ml) and the solution was stirred at ambient temperaturefor about 16 hours. The reaction mixture was concentrated in vacuum downto the water layer, was cooled with an ice bath, and was acidified byaddition of 2N hydrochloric acid. The precipitate was filtered off andwas dried in vacuum to provide the title compound.

Example 22CE-4-[2-(4-Bromo-phenyl)-2-methyl-propionylamino]-adamantane-1-carboxylicacid methyl ester

A solution of the product of Example 22B (3.3 g, 13.5 mmoles), theproduct of Example 1C (3.3 g, 13.5 mmoles),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (8.6g, 26.9 mmoles) and N,N-diisopropylethylamine (9.4 ml, 53.8 mmoles) inN,N-dimethylformamide (150.0 ml) was stirred at room temperature forabout 16 hours under a nitrogen atmosphere. The solvent was evaporatedin vacuum and the residue was purified by flash column chromatography onsilica gel using hexanes/ethyl acetate (2:1) as the mobile phase toprovide the title compound.

Example 22DE-4-[2-Methyl-2-(4-pyridin-4-yl-phenyl)-propionylamino]-adamantane-1-carboxylicacid methyl ester

To a solution of the product of Example 22C (300 mg, 0.7 mmoles) in1,2-dimethoxyethane (6.0 ml) was added a solution of pyridine-4-boronicacid (127 mg, 1.0 mmoles) in ethanol (1.0 ml),dichlorobis(tri-o-tolylphosphine)palladium(II) (28 mg, 0.04 mmoles) anda 2M aqueous solution of sodium carbonate (1.7 ml, 3.5 mmoles) and themixture was stirred under nitrogen in a heavy walled process vial in amicrowave synthesizer (Personal Chemistry Smith Synthesizer) at about140° C. for about 10 min. The reaction mixture was concentrated invacuum and the crude product was purified by flash column chromatographyon silica gel using hexanes/ethyl acetate (2:1) as the mobile phase toprovide the title compound.

Example 22EE-4-[2-Methyl-2-(4-pyridin-4-yl-phenyl)-propionylamino]-adamantane-1-carboxylicacid

To a solution of the product of Example 22D (125 mg, 0.29 mmoles) indioxane (4.0 ml) was added 2N aqueous hydrochloric acid (4.0 ml) and themixture was heated to about 60° C. for about 18 hours. The mixture wascooled, concentrated to dryness and the residue was purified bypreparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μmparticle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueousTFA over 8 min (10 min run time) at a flow rate of 40 mL/min to providethe title compound.

Example 22FE-4-[2-Methyl-2-(4-pyridin-4-yl-phenyl)-propionylamino]-adamantane-1-carboxylicacid amide

A solution of the product of Example 22E (60 mg, 0.14 mmoles),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (110 mg,0.57 mmoles) and 1-hydroxybenzotriazole hydrate (44 mg, 0.32 mmoles) indichloromethane (4.0 ml) was stirred at ambient temperature under anitrogen atmosphere for about 1 hour. A 0.5 M solution of ammonia indioxane (2.9 ml, 1.43 mmoles) was added and stirring was continued forabout 16 hours. The mixture was evaporated to dryness and the residuewas purified by preparative HPLC on a Waters Symmetry C8 column (25mm×100 mm, 7 μm particle size) using a gradient of 10% to 100%acetonitrile:0.1% aqueous TFA over 8 min (10 min run time) at a flowrate of 40 mL/min to provide the title compound as the trifluoroaceticacid salt. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.84-8.86 (m, 2H), 8.17-8.19(m, 2H), 7.94-7.97 (m, 2H), 7.54-7.56 (m, 2H), 6.96-6.98 (bs, 1H),6.70-6.72 (bs, 1H), 6.57 (d, J=6.64 Hz, 1H), 3.76-3.80 (m, 1H),1.90-1.92 (m, 2H), 1.75-1.84 (m, 5H), 1.64-1.75 (m, 4H), 1.55 (s, 6H),1.33-1.37 (m, 2H); MS (ESI+) m/z 418 (M+H)⁺.

Example 23E-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-1-carboxamideExample 23A Ethyl 2-methyl-2-(thiophen-2-yl)propanoate

The title compound was prepared according to the method of Example 22A,substituting ethyl 2-(thiophen-2-yl)acetate for ethyl4-bromophenylacetate.

Example 23B 2-Methyl-2-(thiophen-2-yl)propanoic acid

The title compound was prepared according to the method of Example 22B,substituting the product of Example 23A for the product of Example 22A.

Example 23CE-4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22C,substituting the product of Example 23B for the product of Example 22B.

Example 23DE-4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carboxylicacid

To a solution of the product of Example 23C (250 mg, 0.69 mmoles) indioxane (9.0 ml) was added 2N hydrochloric acid (9.0 ml) and the mixturewas heated to about 60° C. for about 18 hours. The mixture was cooled,concentrated down to the water layer, the precipitate was filtered offand was dried in vacuum to give the title compound.

Example 23EE-4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method of Example 22F,substituting the product of Example 23D for the product of Example 22E.¹H NMR (500 MHz, DMSO-d₆) 5 ppm 7.46 (dd, J=5.10, 1.20 Hz, 1H), 7.10(dd, J=3.52, 1.21 Hz, 1H), 7.02 (dd, J=5.09, 3.52 Hz, 1H), 6.95-6.97(bs, 1H), 6.69-6.71 (bs, 1H), 6.24 (d, J=7.11 Hz, 1H), 3.68-3.72 (m,1H), 1.82-1.84 (m, 2H), 1.72-1.81 (m, 5H), 1.66-1.72 (m, 2H), 1.56 (s,6H), 1.48-1.52 (m, 2H), 1.34-1.38 (m, 2H); MS (ESI+) m/z 347 (M+H)⁺.

Example 24E-4-[(2-methyl-2-thien-3-ylpropanoyl)amino]adamantane-1-carboxamideExample 24A Ethyl 2-methyl-2-(thiophen-3-yl)propanoate

The title compound was prepared according to the method of Example 22Asubstituting ethyl 2-(thiophen-3-yl)acetate for 4-bromophenylacetate.

Example 24B 2-Methyl-2-(thiophen-3-yl)propanoic acid

The title compound was prepared according to the method of Example 22B,substituting the product of Example 24A for the product of Example 22A.

Example 24CE-4-(2-Methyl-2-thiophen-3-yl-propionylamino)-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22C,substituting the product of Example 24B for the product of Example 22B.

Example 24DE-4-(2-Methyl-2-thiophen-3-yl-propionylamino)-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 23D,substituting the product of Example 24C for the product of Example 23C.

Example 24EE-4-(2-Methyl-2-thiophen-3-yl-propionylamino)-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method of Example 22F,substituting the product of Example 24D for the product of Example 22E.¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.54 (dd, J=5.03, 2.90 Hz, 1H), 7.41(dd, J=2.89, 1.44 Hz, 1H), 7.12 (dd, J=5.00, 1.40 Hz, 1H), 6.95-6.97(bs, 1H), 6.69-6.70 (bs, 1H), 6.01-6.07 (m, 1H), 3.68-3.72 (m, 1H),1.76-1.82 (m, 7H), 1.69 (d, J=3.14 Hz, 2H), 1.51 (s, 6H), 1.43-1.48 (m,2H), 1.33-1.37 (m, 2H); MS (ESI+) m/z 347 (M+H)⁺.

Example 25E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamantane-1-carboxamideExample 25A Potassium;2-methyl-2-(5-trifluoromethyl-pyridin-2-yl)-propionate

A solution of 2-chloro-5-(trifluoro-methyl)pyridine (328 mg, 1.8 mmol),methyl trimethylsilyl dimethylketene acetal (0.378 mg, 2.17 mmol), zincfluoride (112 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0)(20 mg, 0.021 mmol) and tri-t-butylphosphine-10 wt % in hexane (172 mg,0.084 mmol) in Argon degassed DMF (1.5 mL) was stirred at 90° C. for 12hours. The reaction was taken up in EtOAc (25 mL) and washed with water(15 mL) followed by brine (15 mL). The organic layer was dried withMgSO₄, filtered, and evaporated in vacuo. The crude product was purifiedby flash chromatography (hexane/EtOAc 100:0 to 80:20) to give the methylester of the title compound. A solution of the methyl ester of the titlecompound (180 mg, 0.73 mmol), potassium trimethylsilanolate (KOTMS) (140mg, 1.1 mmol) in THF (2 mL) was stirred for 12 hours at 23° C. Methylt-butyl ether (MTBE) 8 mL was added to the solution and the titlecompound was isolated by filtration.

Example 25BE-4-[2-Methyl-2-(5-trifluoromethyl-pyridin-2-yl)-propionylamino]-adamantane-1-carboxylicacid methyl ester

A solution of the product of Example 25A (50 mg, 0.184 mmol), theproduct of Example IC (54 mg, 0.22 mmol), TBTU (94 mg, 0.294 mmol) andDIEA (58 mg, 0.46 mmol) in DMF (1.2 mL) was stirred for 3 hrs at 23° C.The reaction was diluted with EtOAc (10 mL) and washed twice with water(6 mL) and brine (6 mL). The organic layer was dried with MgSO₄,filtered and evaporated in vacuo to afford the title compound. Theproduct was carried to the next step without further purification.

Example 25CE-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamantane-1-carboxamide

A solution of Example 25B (30 mg, 0.071 mmol), KOTMS (14 mg, 0.11 mmol)in THF (1 mL) was stirred for 12 hours at 23° C. The solvent wasevaporated in vacuo to collect a solid. To the solid was added TBTU (40mg, 0.12 mmol), DIEA (22 mg, 0.17 mmol) and DMF (0.5 mL) and stirred for2 hours at 23° C. Ammonium hydroxide-30% by weight (2 mL) was added andstirred at 23° C. for a further 30 minutes. The reaction was partitionedbetween EtOAc (8 mL) and water (3 mL). The organic layer was washed withwater (3 mL), dried with MgSO₄, filtered, and evaporated in vacuo. Thecrude reaction mixture was purified by preparative reverse phase HPLC ona Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using agradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at aflow rate of 40 mL/min. to provide the title compound as thetrifluoroacetic acid salt. ¹H NMR (500 MHz, Chloroform-d₁) δ ppm8.86-8.87 (m, 1H), 7.94 (dd, J=8.38, 2.40 Hz, 1H), 7.59 (d, J=8.33 Hz,1H), 7.41 (d, J=7.48 Hz, 1H), 6.13-6.18 (bs, 1H), 5.80-5.84 (bs, 1H),3.93-3.97 (m, 1H), 1.99-2.03 (m, 3H), 1.93-1.99 (m, 4H), 1.87-1.89 (m,2H), 1.69 (s, 6H), 1.63-1.68 (m, 2H), 1.56-1.60 (m, 2H); MS (APCI+) m/z410 (M+H)⁺.

Example 26 E-4-[(2-methyl-2-{4-[5-(trifluoro methyl)pyridin-2yl]phenyl}propanoyl)amino]adamantane-1-carboxamide Example 26A Ethyl2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

A mixture of the product of Example 22A (500 mg, 1.84 mmoles),bis(pinacolato)diboron (735 mg, 2.90 mmoles),1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (90 mg, 0.11mmoles) and potassium acetate (903 mg, 9.20 mmoles) in dimethylsulfoxide (11.0 ml) was heated to about 80° C. under a nitrogenatmosphere for about two days. The mixture was cooled, diluted withbenzene (28.0 ml) and was washed three times with water (18.0 ml each).The organic layer was dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure and the crude product was purifiedby flash column chromatography on silica gel using hexanes/ethyl acetate(2:1) as the mobile phase to provide the title compound.

Example 26B Ethyl2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)propanoate

To a solution of the product of Example 26A (370 mg, 1.16 mmoles) and2-bromo-5-(trifluoromethyl)pyridine (341 mg, 1.51 mmoles) inN,N-dimethylformamide (10.0 ml) were added1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04mmoles) and a 2M aqueous solution of sodium carbonate (1.7 ml, 3.48mmoles) and the reaction mixture was heated under a nitrogen atmosphereto about 80° C. for about 1 hour. Another portion of1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04mmoles) was added and the mixture was heated to about 90° C. for about 2hours. The solvent was evaporated in high vacuum, the residue was takenup in water (20.0 ml) and diethyl ether (20.0 ml), and was filteredthrough Celite. The layers were separated and the aqueous layer wasextracted with diethyl ether. The combined organic extracts were driedover MgSO₄ and filtered. The filtrate was concentrated under reducedpressure and the crude product was purified by flash columnchromatography on silica gel using hexanes/ethyl acetate (2:1) as themobile phase to provide the title compound.

Example 26C2-Methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)propanoic acid

The title compound was prepared according to the method of Example 22B,substituting the product of Example 26B for the product of Example 22A.

Example 26DE-4-{2-Methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-propionylamino}-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22Csubstituting the product of Example 26C for the product of Example 22B.

Example 26EE-4-{2-Methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-propionylamino}-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 22Esubstituting the product of Example 26D for the product of Example 22D.

Example 26FE-4-{2-Methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-propionylamino}-adamantane-1-carboxylicacid amide

The trifluoroacetic acid salt of the title compound was preparedaccording to the method of Example 22F substituting the product ofExample 26E for the product of Example 22E. ¹H NMR (500 MHz, DMSO-d₆) δppm 9.03-9.05 (m, 1H), 8.27 (dd, J=8.46, 2.42 Hz, 1H), 8.20 (d, J=8.38Hz, 1H), 8.13-8.16 (m, 2H), 7.50-7.53 (m, 2H), 6.96-6.98 (bs, 1H),6.69-6.71 (bs, 1H), 6.48 (d, J=6.75 Hz, 1H), 3.76-3.81 (m, 1H),1.88-1.91 (m, 2H), 1.74-1.84 (m, 5H), 1.60-1.74 (m, 4H), 1.54 (s, 6H),1.32-1.36 (m, 2H); MS (ESI+) m/z 486 (M+H)⁺.

Example 27E-4-({[1-(4-methoxyphenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamideExample 27AE-4-{[1-(4-Methoxy-phenyl)-cyclopentanecarbonyl]-amino}-adamantane-1-carboxylicacid methyl etser

A solution of the product of Example 1C (110 mg, 0.45 mmol),1-(4-methoxyphenyl)-1-cyclopentanecarboxylic acid (100 mg, 0.45 mmol),and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (219 mg, 0.68 mmol) in N,N-dimethylformamide (DMF) (2 mL) wasstirred ten minutes at room temperature, and then, diisopropylethylamine(240 μL, 1.4 mmol) was added. Reaction stirred for 16 hours at roomtemperature. The reaction was diluted with ethyl acetate and washedsuccessively with water, saturated sodium bicarbonate, 1N phosphoricacid, and brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with 20-30% ethyl acetate/hexane to provide the titlecompound.

Example 27BE-4-{[1-(4-Methoxy-phenyl)-cyclopentanecarbonyl]-amino}-adamantane-1-carboxylicacid

A solution of the product of Example 27A (160 mg, 0.39 mmol) in THF (3mL) was treated with aqueous 4N sodium hydroxide (1.00 mL, 3.9 mmol) andmethanol (1 mL), and reaction stirred 16 hours at room temperature. Thereaction mixture was concentrated under reduced pressure, and theresidue was taken up in water. The solution was acidified to pH 3 by theaddition of aqueous 1N phosphoric acid, and the product was extractedwith chloroform (3×). The combined extracts were dried (Na₂SO₄),filtered, and concentrated under reduced pressure to provide the titlecompound.

Example 27CE-4-{[1-(4-Methoxy-phenyl)-cyclopentanecarbonyl]-amino}-adamantane-1-carboxylicacid amide

A solution of the product of Example 27B (130 mg, 0.330 mmol),1-hydroxybenzotriazole (54 mg, 0.40 mmol), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (76mg, 0.40 mmol) in dimethylformamide (5 mL) was stirred two hours at roomtemperature. The reaction was treated with concentrated ammoniumhydroxide (1 mL) and stirred 16 hours at room temperature. Reactiondiluted with ethyl acetate and washed successively with water, saturatedsodium bicarbonate, 1N phosphoric acid, and brine before drying overNa₂SO₄, filtering, and concentrating under reduced pressure. Residuepurified by flash chromatography on silica gel eluting with 5%methanol/ethyl acetate to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.29-7.31 (m, 2H), 6.94-6.95 (bs, 1H), 6.86-6.89 (m, 2H),6.68-6.69 (bs, 1H), 6.32 (d, J=6.82 Hz, 1H), 3.73 (s, 3H), 3.64-3.70 (m,1H), 2.46-2.51 (m, 2H), 1.74-1.85 (m, 9H), 1.68 (d, J=3.12 Hz, 2H),1.53-1.62 (m, 6H), 1.30-1.34 (m, 2H); MS (ESI+) m/z 397 (M+H)⁺.

Example 28E-4-{[2-(4-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamideExample 28AE-4-[2-(4-Bromo-phenyl)-2-methyl-propionylamino]-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 23Dsubstituting the product of Example 22C for the product of Example 23C.

Example 28BE-4-[2-(4-Bromo-phenyl)-2-methyl-propionylamino]-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method of Example 22Fsubstituting the product of Example 28A for the product of Example 22E.NMR (400 MHz, DMSO-d₆) δ ppm 7.50-7.53 (m, 2H), 7.27-7.30 (m, 2H),6.93-6.95 (bs, 1H), 6.65-6.68 (bs, 1H), 6.43 (d, J=6.73 Hz, 1H),3.72-3.76 (m, 1H), 1.86-1.89 (m, 2H), 1.77-1.79 (m, 5H), 1.61-1.73 (m,4H), 1.47 (s, 6H), 1.32-1.37 (m, 2H); MS (DCI) m/z 419, 421 (M+H)⁺.

Example 30 E-4-[5-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopiperidine-3-carboxamideExample 30A 2-But-3-enyl-2-methyl-malonic acid dimethyl ester

A stirred solution of NaH-60% by weight (0.517 gm, 12.94 mmol) in DMF (5mL) was cooled to 0° C. and dimethyl methyl malonate (1.26 gm, 8.63mmol) in 3 mL of DMF was added dropwise. The reaction was warmed toambient and stirred for 15 minutes. A solution of 4-bromo-1-butene (1.28gm, 9.49 mmol) in 1.5 mL of DMF was added to the reaction mixture andstirred for 12 hours at 23° C. The reaction was partitioned between 10%NH₄Cl (20 mL) and 30 mL of EtOAc. The organic layer was washed withwater (20 mL), brine (20 mL), dried with MgSO₄, filtered and evaporatedin vacuo. The crude product was purified by flash chromatography(hexane/EtOAc 100:0 to 85:15) to provide Example 30A as an oil.

Example 30B 2-Methyl-2-(3-oxo-propyl)-malonic acid dimethyl ester

A solution of the product of Example 30A (1.0 gm, 5 mmol) was dissolvedin CH₂Cl₂/MeOH 10:1 (15 mL) and cooled to −78° C. To the solution wasbubbled O₃ over 20 minutes. The reaction solution was purged with N₂ fora further 10 minutes and dimethyl sulfide (DMS) (3.1 gm, 50 mmol) wasadded and the reaction warmed to ambient temperature and stirred for afurther 2 hours. The solvent was evaporated in vacuo and productpurified by flash column chromatography (hexane/EtOAc 100:0 to 70:30) tocollect Example 30B as an oil.

Example 30C Potassium;3-Methyl-1-(2-methyl-benzyl)-2-oxo-piperidine-3-carboxylate

A solution of the product of Example 30B (0.075 gm, 0.37 mmol),2-methyl-benzylamine (53 mg, 0.44 mmol) and MP-triacetoxy borohydride(420 mg, 0.92 mmol) in THF (2 mL) was stirred for 12 hours at 23° C. Thesolution was filtered and evaporated in vacuo. The resulting oil wastaken up in THF (1.2 mL) and stirred with KOTMS (71 mg, 0.55 mmol) at23° C. for 12 hours. The solvent was evaporated in vacuo to provide thetitle compound as a white solid.

Example 30DE-[4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopiperidine-3-carboxamide

A solution of the product of Example 30 C (50 mg, 0.167 mmol), theproduct of Example 1C (49 mg, 0.2 mmol), TBTU (85 mg, 0.26 mmol) andDIEA (53 mg, 0.42 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23°C. The reaction was partitioned between EtOAc (8 ml) and water (4 ml).The organic layer was separated and washed twice with water (4 mL each),dried with MgSO₄, filtered and evaporated in vacuo. The resulting oilwas taken in THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) at 23°C. for 12 hours. The solvent was evaporated in vacuo. The resultingsolid was taken in DMF (1 mL) and stirred with TBTU (96 mg, 0.3 mmol)and DIEA (53 mg, 0.42 mmol) for 2 hours at 23° C. Ammonium hydroxide-30%by weight (2 mL) was added and stirred for a further 30 minutes at 23°C. The reaction was partitioned between EtOAc (8 mL) and water (3 mL).The organic layer was washed with water (3 mL), dried with MgSO₄ andevaporated in vacuo. The crude reaction mixture was purified bypreparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 20% to 100%acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.25 (d,J=8.1 Hz, 1H), 7.19 (m, 2H), 7.13 (m, 1H), 7.02 (d, J=7.5 Hz, 1H), 6.6(bs, 1H), 5.82 (bs, 1H), 4.93 (d, J=15.3, 1H), 4.38 (d, J=15.3, 1H),4.01 (m, 1H), 3.22 (m, 2H), 2.67 (m, 1H), 2.28 (s, 3H), 2.1 (m, 1H),1.99 (m, 6H), 1.81 (m, 5H), 1.57 (m, 2H), 1.56 (s, 3H); MS (APCI) m/z438 (M+H)

Example 31E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopyrrolidine-3-carboxamideExample 31A 2-Allyl-2-methyl-malonic acid dimethyl ester

A stirred solution of NaH-60% by weight (0.493 gm, 12.34 mmol) in DMF (5mL) was cooled to 0° C. and dimethyl methyl malonate (1.2 gm, 8.23 mmol)in 3 mL of DMF was added dropwise. The reaction was warmed to ambienttemperature and stirred for 15 minutes. A solution of allyl bromide(1.18 gm, 9.86 mmol) in 1.5 nit of DMF was added to the reaction mixtureand stirred for 12 hours at 23° C. The reaction was partitioned between10% NH₄Cl (20 mL) and 30 mL of EtOAc. The organic layer was washed withwater (20 mL), brine (20 mL), dried with MgSO₄, filtered and evaporatedin vacuo. The crude product was purified by flash chromatography(hexane/EtOAC 100:0 to 85:15) to provide the title compound as an oil.

Example 31B 2-Methyl-2-(2-oxo-ethyl)-malonic acid dimethyl ester

A solution of the product of Example 31A (1.1 gm, 5.9 mmol) wasdissolved in CH₂Cl₂/MeOH 10:1 (15 mL) and cooled to −78° C. To thesolution was bubbled O₃ over 20 minutes. The reaction solution waspurged with N₂ for a further 10 minutes and dimethyl sulfide (DMS) (3.6gm, 59 mmol) was added and the reaction warmed to ambient temperatureand stirred for a further 2 hours. The solvent was evaporated in vacuoand product purified by flash column chromatography (hexane/EtOAc 100:0to 70:30) to collect Example 31B as an oil.

Example 31C Potassium; 1-benzyl-3-methyl-2-oxo-pyrrolidine-3-carboxylate

A solution of the product of Example 31B (0.075 gm, 0.4 mmol),benzylamine (51 mg, 0.47 mmol) and MP-triacetoxy borohydride (431 mg, 1mmol) in THF (2 mL) was stirred for 12 hours at 23° C. The solution wasfiltered and evaporated in vacuo. The resulting oil was taken up in THF(1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23° C.The solvent was evaporated in vacuo to provide Example 31C.

Example 31DE-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopyrrolidine-3-carboxamide

A solution of the product of Example 31C (50 mg, 0.18 mmol), the productof Example 1C (54 mg, 0.22 mmol), TBTU (92 mg, 0.29 mmol) and DIEA (57mg, 0.45 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23° C. Thereaction was partitioned between EtOAc (8 ml) and water (4 ml). Theorganic layer was separated and washed twice with water (4 mL each),dried with MgSO₄, filtered and evaporated in vacuo. The resulting oilwas taken in THF (1 mL) and stirred with KOTMS (34 mg, 0.27 mmol) for 12hours at 23° C. The solvent was evaporated in vacuo. The resulting solidwas taken in DMF (1 mL) and stirred with TBTU (104 mg, 0.32 mmol) andDIEA (57 mg, 0.45 mmol) for 2 hours at 23° C. Ammonium hydroxide-30% byweight (2 mL) was added and stirred for a further 30 minutes. Thereaction was partitioned between EtOAc (8 mL) and water (3 mL). Theorganic layer was washed with water (3 mL), dried with MgSO₄ andevaporated in vacuo. The crude reaction mixture was purified bypreparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 20% to 100%acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound. ¹H NMR (400 MHz, Chloroform-d₁) δ ppm8.18-8.23 (m, 1H), 7.29-7.35 (m, 3H), 7.19-7.21 (m, 2H), 5.48-5.70 (m,2H), 4.51 (d, J=14.73 Hz, 1H), 4.43 (d, J=14.58 Hz, 1H), 3.99-4.05 (m,1H), 3.14-3.21 (m, 2H), 2.60-2.68 (m, 1H), 2.09-2.15 (m, 1H), 2.01-2.09(m, 2H), 1.87-2.00 (m, 8H), 1.84-1.86 (m, 1H), 1.57-1.66 (m, 2H), 1.48(s, 3H); MS (APCI) m/z 410 (M+H)

Example 32E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopyrrolidine-3-carboxamideExample 32A Potassium;3-methyl-1-(2-methyl-benzyl)-2-oxo-pyrrolidine-3-carboxylate

A solution of the product of Example 31B (0.075 gm, 0.4 mmol),2-methyl-benzylamine (58 mg, 0.47 mmol) and MP-triacetoxy borohydride(431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23° C. Thesolution was filtered and evaporated in vacuo. The resulting oil wastaken up in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12hours at 23° C. The solvent was evaporated in vacuo to provide Example32A.

Example 32BE-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopyrrolidine-3-carboxamide

A solution of Example 32A (50 mg, 0.17 mmol), the product of Example 1C(52 mg, 0.21 mmol), TBTU (87 mg, 0.27 mmol) and DIEA (54 mg, 0.42 mmol)in DMF (1.2 mL) was stirred for 2 hours at 23° C. The reaction waspartitioned between EtOAc (8 ml) and water (4 ml). The organic layer wasseparated and washed twice with water (4 mL each), dried with MgSO₄,filtered and evaporated in vacuo. The resulting oil was taken in THF (1mL) and stirred with KOTMS (33 mg, 0.25 mmol) for 12 hours at 23° C. Thesolvent was evaporated in vacuo. The resulting solid was taken in DMF (1mL) and stirred with TBTU (98 mg, 0.31 mmol) and DIEA (54 mg, 0.42 mmol)for 2 hours. Ammonium hydroxide-30% by weight (2 mL) was added andstirred for a further 30 minutes at 23° C. The reaction was partitionedbetween EtOAc (8 mL) and water (3mL). The organic layer was washed withwater (3 mL), dried with MgSO₄ and evaporated in vacuo. The crudereaction mixture was purified by preparative reverse phase HPLC on aWaters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using agradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at aflow rate of 40 mL/min. to provide the title compound. ¹H NMR (400 MHz,Chloroform-d₁) δ ppm 8.17-8.22 (m, 1H), 7.12-7.24 (m, 3H), 7.08-7.11 (m,1H), 5.56-5.66 (m, 1H), 5.34-5.43 (m, 1H), 4.50-4.51 (m, 2H), 3.99-4.05(m, 1H), 3.07-3.17 (m, 2H), 2.65 (ddd, J=13.33, 8.70, 7.16 Hz, 1H), 2.28(s, 3H), 2.08-2.15 (m, 1H), 1.81-2.07 (m, 1H), 1.53-1.68 (m, 2H), 1.49(s, 3H); MS (APCI) m/z 424 (M+H)

Example 33E-4-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxo-pyrrolidine-3-carboxamideExample 33A Potassium;1-(2-chloro-benzyl)-methyl-2-oxo-pyrrolidine-3-carboxylate

A solution of the product of 31B (0.075 gm, 0.4 mmol),2-chloro-benzylamine (68 mg, 0.47 mmol) and MP-triacetoxy borohydride(431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23° C. Thesolution was filtered and evaporated in vacuo. The resulting oil wastaken up in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12hours at 23° C. The solvent was evaporated in vacuo to provide Example33A.

Example 33BE-4-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3-carboxamide

A solution of the product of Example 33A (50 mg, 0.16 mmol), the productof Example 1C (48 mg, 0.19 mmol), TBTU (82 mg, 0.25 mmol) and DIEA (51mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23° C. Thereaction was partitioned between EtOAc (8 ml) and water (4 ml). Theorganic layer was separated and washed twice with water (4 mL each),dried with MgSO₄, filtered and evaporated in vacuo. The resulting oilwas taken in THF (1 mL) and stirred with KOTMS (31 mg, 0.24 mmol) for 12hours at 23° C. The solvent was evaporated in vacuo. The resulting solidwas taken in DMF (1 mL) and stirred with TBTU (92 mg, 0.29 mmol) andDIEA (51 mg, 0.4 mmol) for 2 hours at 23° C. Ammonium hydroxide-30% byweight (2 mL) was added and stirred at 23° C. for a further 30 minutes.The reaction was partitioned between EtOAc (8 mL) and water (3 mL). Theorganic layer was washed with water (3 mL), dried with MgSO₄ andevaporated in vacuo. The crude reaction mixture was purified bypreparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 20% to 100%acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound. ¹H NMR (400 MHz, Chloroform-d₁) δ ppm8.13-8.19 (m, 1H), 7.34-7.41 (m, 1H), 7.19-7.28 (m, 3H), 5.60-5.65 (bs,1H), 5.54-5.60 (bs, 1H), 4.62-4.64 (m, 2H), 3.99-4.05 (m, 1H), 3.15-3.30(m, 2H), 2.63-2.73 (m, 1H), 2.09-2.15 (m, 1H), 1.80-2.08 (m, 11H),1.53-1.66 (m, 2H), 1.49 (s, 3H); MS (PCI) m/z 444 (M+H).

Example 34E-4-(aminocarbonyl)-2-adamantyl]-1-(3-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3-carboxamideExample 34A Potassium;1-(3-chloro-benzyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylate

A solution of the product of Example 31B (0.075 gm, 0.4 mmol),3-chloro-benzylamine (68 mg, 0.47 mmol) and MP-triacetoxy borohydride(431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23° C. Thesolution was filtered and evaporated in vacuo. The resulting oil wastaken up in THF (1.2 mL) and stirred with KOTMS (77 mg, 0.6 mmol) at 23°C. for 12 hours. The solvent was evaporated in vacuo to provide Example34A.

Example 34BE-4-(aminocarbonyl)-2-adamantyl]-1-(3-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3-carboxamide

A solution of the product of Example 34A (50 mg, 0.16 mmol), the productof Example 1C (48 mg, 0.19 mmol), TBTU (82 mg, 0.25 mmol) and DIEA (51mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23° C. Thereaction was partitioned between EtOAc (8 ml) and water (4 ml). Theorganic layer was separated and washed twice with water (4 mL each),dried with MgSO₄, filtered and evaporated in vacuo. The resulting oilwas taken in THF (1 mL) and stirred with KOTMS (31 mg, 0.24 mmol) at 23°C. for 12 hours. The solvent was evaporated in vacuo. The resultingsolid was taken in DMF (1 mL) and stirred with TBTU (92 mg, 0.29 mmol)and DIEA (51 mg, 0.4 mmol) for 2 hours at 23° C. Ammonium hydroxide-30%by weight (2 mL) was added and stirred at 23° C. for a further 30minutes. The reaction was partitioned between. EtOAc (8 mL) and water (3mL). The organic layer was washed with water (3 mL), dried with MgSO₄and evaporated in vacuo. The crude reaction mixture was purified bypreparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 20% to 100%acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound. ¹H NMR (400 MHz, Chloroform-d₁) δ ppm8.11 (d, J=7.93 Hz, 1H), 7.26-7.29 (m, 2H), 7.18-7.20 (m, 1H), 7.07-7.10(m, 1H), 5.64-5.79 (m, 2H), 4.44 (s, 2H), 3.99-4.04 (m, 1H), 3.18-3.23(m, 2H), 2.68 (ddd, J=15.66, 8.55, 7.17 Hz, 1H), 2.02-2.15 (m, 3H),1.88-2.02 (m, 8H), 1.81-1.88 (m, 1H), 1.58-1.66 (m, 2H), 1.49 (s, 3H);MS (APCI) m/z 444.

Example 35E-4-({2-methyl-2-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-1-carboxamideExample 35AE-4-{2-Methyl-2-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-propionylamino}-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22Dsubstituting1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole forpyridine-4-boronic acid.

Example 35BE-4-{2-Methyl-2-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-propionylamino}-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 23D,substituting the product of Example 35A for the product of Example 23C.

Example 35CE-4-{2-Methyl-2-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-propionylamino}-adamantane-1-carboxylicacid amide

A solution of the product of Example 35B (240 mg, 0.55 mmoles),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (421 mg,2.2 mmoles) and 1-hydroxybenzotriazole hydrate (167 mg, 1.24 mmoles) indichloromethane (19 ml) was stirred at ambient temperature under anitrogen atmosphere for about 1 hour. A 0.5 M solution of ammonia indioxane (11.0 ml, 5.50 mmoles) was added and stirring was continued forabout 2 hours. Ammonium hydroxide (9.5 ml) was added to the reactionmixture and stirring was continued for about 2 hours. The mixture wasdiluted with dichloromethane (60 ml), the layers were separated, theorganic layer was dried (MgSO₄), filtered and the filtrate wasevaporated in vacuum. The residue was purified by flash columnchromatography on silica gel using dichloromethane/methanol (15:1) asthe mobile phase to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.11 (s, 1H), 7.83 (s, 1H), 7.51-7.53 (m, 2H), 7.31-7.33(m, 2H), 6.95-6.97 (bs, 1H), 6.69-6.71 (bs, 1H), 6.28 (d, J=6.87 Hz,1H), 3.85 (s, 3H), 3.74-3.78 (m, 1H), 1.84-1.89 (m, 2H), 1.73-1.82 (m,5H), 1.67-1.70 (m, 2H), 1.54-1.60 (m, 2H), 1.49 (s, 6H), 1.31-1.37 (m,2H); MS (ESI+) m/z 421 (M+H)⁺.

Example 36E-4-{[2-(3-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamideExample 36A (3-Bromophenyl)-acetic acid methyl ester

A solution of 3-bromophenylacetic acid (2.0 g, 9.3 mmol) and4-dimethylamino pyridine (1.1 g, 9.3 mmol) in methanol (20 mL) wastreated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDAC) (2.1 g, 11 mmol). Reaction stirred for 16 hours atroom temperature. The reaction mixture was concentrated under reducedpressure. The residue was taken up in ethyl acetate and washed withwater, saturated sodium bicarbonate, 1N phosphoric acid, and brinebefore drying over Na₂SO₄, filtering, and concentrating under reducedpressure to provide the title compound.

Example 36B 2-(3-Bromophenyl)-2-methylpropionic acid methyl ester

A 0° C. solution of the product of Example 36A (2.1 g, 9.3 mmol) inanhydrous dimethylformamide (20 mL) was treated portion-wise with 60%sodium hydride (890 mg, 22 mmol) in mineral oil. The reaction mixturewas stirred for twenty minutes at 0° C., and methyl iodide (1.4 mL, 22mmol) was then added. Ice bath was removed, and reaction mixture stirred16 hours at room temperature. Reaction mixture quenched with saturatedammonium chloride, and product extracted with ethyl acetate (2×). Thecombined extracts were washed with water and brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. Residue purified bynormal phase HPLC on silica gel eluting with 10% ethyl acetate/hexane toprovide the title compound.

Example 36C 2-(3-Bromophenyl)-2-methylpropionic acid

The title compound was prepared according to the method as described inExample 27B, substituting the product of Example 36B for the product ofExample 27A.

Example 36DE-4-[2-(3-Bromophenyl)-2-methylpropionylamino]-adamantane-1-carboxylicacid methly ester

The title compound was prepared according to the method as described inExample 27A, substituting the product of Example 36C for1-(4-methoxyphenyl)-1-cyclopentanecarboxylic acid.

Example 36EE-4-[2-(3-Bromophenyl)-2-methylpropionylamino]-adamantane-1-carboxylicacid

The title compound was prepared according to the method as described inExample 27B, substituting the product of Example 36D for the product ofExample 27A.

Example 36FE-4-[2-(3-Bromophenyl)-2-methylpropionylamino]-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method as described inExample 27C, substituting the product of Example 36E for the product ofExample 27B. ¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (m, 1H), 7.42 (m, 1H),7.20 (m, 2H), 6.95 (bs, 1H), 6.66 (bs, 1H), 6.32 (d, J=6 Hz, 1H), 3.77(m, 1H), 1.95-1.60 (m, 11H), 1.47 (s, 6H), 1.33 (m, 2H); MS (ESI+) m/z419 (M+H)⁺.

Example 37E-4-({2-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxamideExample 37AE-4-{2-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-2-methyl-propionylamino}-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22D,substituting3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)isoxazolefor pyridine-4-boronic acid.

Example 37BE-4-{2-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-2-methyl-propionylamino}-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 23D,substituting the product of Example 37A for the product of Example 23C.

Example 37CE-4-{2-[1-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-2-methyl-propionylamino}-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method of 35C,substituting the product of Example 37B for the product of Example 35B.The crude product was purified by preparative HPLC on a Waters SymmetryC8 column (25 mm×100 mm, 7 gm particle size) using a gradient of 10% to100% acetonitrile:0.1% aqueous TFA over 8 min (10 min run time) at aflow rate of 40 mL/min. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.44-7.46 (m,2H), 7.35-7.37 (m, 2H), 6.95-6.97 (bs, 1H), 6.69-6.71 (bs, 1H), 6.35 (d,J=6.87 Hz, 1H), 3.74-3.78 (m, 1H), 2.38 (s, 3H), 2.21 (s, 3H), 1.87-1.89(m, 2H), 1.73-1.83 (m, 5H), 1.67-1.73 (m, 2H), 1.56-1.60 (m, 2H), 1.53(s, 6H), 1.32-1.36 (m, 2H); MS (ESI+) m/z 436 (M+H)⁺.

Example 38E-4-{[2-methyl-2-(4-pyridin-3-ylphenyl)propanoyl]amino}adamantane-1-carboxamideExample 38AE-4-[2-Methyl-2-(4-pyridin-3-yl-phenyl)-propionylamino]-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22D,substituting pyridine-3-boronic acid for pyridine-4-boronic acid.

Example 38BE-4-[2-Methyl-2-(4-pyridin-3-yl-phenyl)-propionylamino]-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 22Esubstituting the product of Example 38A for the product of Example 22D.

Example 38CE-4-[2-Methyl-2-(4-pyridin-3-yl-phenyl)-propionylamino]-adamantane-1-carboxylicacid amide

The trifluoroacetic acid salt of the title compound was preparedaccording to the method of Example 35C, substituting the product ofExample 38B for the product of Example 35B, and with the exception thatthe crude product was purified by preparative HPLC on a Waters SymmetryC8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to100% acetonitrile:0.1% aqueous TFA over 8 min (10 min run time) at aflow rate of 40 ml/min. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.07-9.08 (bs,1H), 8.72 (d, J=5.06 Hz, 1H), 8.47 (d, J=8.03 Hz, 1H), 7.77-7.83 (m,3H), 7.50-7.53 (m, 2H), 6.94-6.96 (bs, 1H), 6.66-6.69 (bs, 1H), 6.48 (d,J=6.68 Hz, 1H), 3.76-3.81 (m, 1H), 1.89-1.92 (m, 2H), 1.78-1.84 (m, 5H),1.65-1.71 (m, 4H), 1.54 (s, 6H), 1.33-1.38 (m, 2H); MS (ESI+) m/z 418(M+H)⁺.

Example 394-{[({(E)-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoicacid Example 39AE-4-({[4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carbonyl]-amino}-methyl)-benzoicacid methyl ester

The title compound was prepared according to the method of Example 22C,substituting the product of Example 23D for Example 22B and substitutingmethyl 4-(aminomethyl)-benzoate hydrochloride for the product of Example1C.

Example 39BE-4-({[4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carbonyl]-amino}-methyl)-benzoicacid

The title compound was prepared according to the method of Example 22B,substituting the product of Example 39A for the product of Example 22A.¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.70-12.94 (bs, 1H), 8.04-8.09 (m, 1H),7.85-7.88 (m, 2H), 7.46 (dd, J=5.06, 1.22 Hz, 1H), 7.28-7.36 (m, 2H),7.10 (dd, J=3.52, 1.23 Hz, 1H), 7.02 (dd, J=5.08, 3.54 Hz, 1H), 6.25 (d,J=7.10 Hz, 1H), 4.30 (d, J=5.87 Hz, 2H), 3.71-3.76 (m, 1H), 1.75-1.86(m, 9H), 1.57 (s, 6H), 1.48-1.55 (m, 2H), 1.37-1.42 (m, 2H); MS (ESI+)m/z 481 (M+H)⁺.

Example 40E-4-({2-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-1-carboxamideExample 40AE-4-{2-Methyl-2-[1H-pyrazol-4-yl)-phenyl]-propionylamino}-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22Dsubstituting1-tert-butoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolefor pyridine-4-boronic acid.

Example 40BE-4-{2-Methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propionylamino}-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 22Esubstituting the product of Example 40A for the product of Example 22D.

Example 40CE-4-{2-Methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propionylamino}-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method of Example 35Csubstituting the product of Example 40B for the product of Example 35B.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.03 (s, 2H), 7.55-7.58 (m, 2H),7.31-7.34 (m, 2H), 6.92-6.96 (bs, 1H), 6.65-6.68 (bs, 1H), 6.25 (d,J=6.95 Hz, 1H), 5.15-5.94 (bs, 1H), 3.73-3.78 (m, 1H), 1.85-1.88 (m,2H), 1.73-1.83 (m, 5H), 1.68-1.70 (m, 2H), 1.55-1.60 (m, 2H), 1.49 (s,6H), 1.31-1.36 (m, 2H); MS (ESI+) m/z 407 (M+H)⁺.

Example 41E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(1-methyl-1-phenylethyl)-2-oxopyrrolidine-3-carboxamideExample 41A Potassium;3-methyl-1-(1-methyl-1-phenyl-ethyl)-2-oxo-pyrrolidine-3-carboxylate

A solution of the product of Example 31B (0.075 gm, 0.4 mmol),1-methyl-1-phenylethylamine (65 mg, 0.47 mmol) and MP-triacetoxyborohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at23° C. The solution was filtered and evaporated in vacuo. The resultingoil was taken up in toluene (1.5 mL) and heated at 100° C. for 5 hours.The solvent was evaporated in vacuo and the residue taken in THF (1.2mL) and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23° C. Thesolvent was evaporated in vacuo to provide Example 41A.

Example 41BE-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(1-methyl-1-phenylethyl)-2-oxopyrrolidine-3-carboxamide

A solution of the product of Example 41A (50 mg, 0.16 mmol), the productof Example IC (48 mg, 0.19 mmol), TBTU (82 mg, 0.25 mmol) and DIEA (51mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23° C. Thereaction was partitioned between EtOAc (8 ml) and water (4 ml). Theorganic layer was separated and washed twice with water (4 mL each),dried with MgSO₄, filtered and evaporated in vacuo. The resulting oilwas taken in THF (1 mL) and stirred with KOTMS (31 mg, 0.24 mmol) for 12hours at 23° C. The solvent was evaporated in vacuo. The resulting solidwas taken in DMF (1 mL) and stirred with TBTU (92 mg, 0.29 mmol) andDIEA (51 mg, 0.4 mmol) for 2 hours at 23° C. Ammonium hydroxide-30% byweight (2 mL) was added and stirred for a further 30 minutes. Thereaction was partitioned between EtOAc (8 mL) and water (3 mL). Theorganic layer was washed with water (3 mL), dried with MgSO₄ andevaporated in vacuo. The crude reaction mixture was purified bypreparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 20% to 100%acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound. ¹H NMR (500 MHz, Chloroform-d₁) δ ppm7.94 (d, J=7.78 Hz, 1H), 7.27-7.34 (m, 4H), 7.21-7.25 (m, 1H), 5.98-6.02(bs, 1H), 5.69-5.73 (bs, 1H), 3.95-4.00 (m, 1H), 3.39-3.47 (m, 2H), 2.69(ddd, J=13.17, 8.02, 6.58 Hz, 1H), 2.03-2.06 (m, 1H), 1.94-2.01 (m, 6H),1.91 (ddd, J=13.24, 7.44, 5.76 Hz, 1H), 1.86-1.88 (m, 2H), 1.76-1.81 (m,1H), 1.75 (s, 3H), 1.72 (s, 3H), 1.64-1.69 (m, 1H), 1.47-1.56 (m, 2H),1.43 (s, 3H); MS (APCI) m/z 438 (M+H).

Example 42E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxamideExample 42A Potassium;3-methyl-2-oxo-1-((1R)-1-phenylethyl)pyrrolidine-3-carboxylate

A solution of the product of Example 31B (0.075 gm, 0.4 mmol),(R)-1-phenylethylamine (58 mg, 0.47 mmol) and MP-triacetoxy borohydride(431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23° C. Thesolution was filtered and evaporated in vacuo. The resulting oil wastaken up in toluene (1.5 mL) and heated at 100° C. for 5 hours. Thesolvent was evaporated in vacuo and the residue taken in THF (1.2 mL)and stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23° C. Thesolvent was evaporated in vacuo to provide Example 42A as 1:1 mixture ofdiastereomers.

Example 42BE-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxamide

A solution of the product of Example 42A (50 mg, 0.17 mmol), the productof Example IC (52 mg, 0.21 mmol), TBTU (87 mg, 0.27 mmol) and DIEA (51mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23° C. Thereaction was partitioned between EtOAc (8 ml) and water (4 ml). Theorganic layer was separated and washed twice with water (4 mL each),dried with MgSO₄, filtered and evaporated in vacuo. The resulting oilwas taken in THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) for 12hours at 23° C. The solvent was evaporated in vacuo. The resulting solidwas taken in DMF (1 mL) and stirred with TBTU (98 mg, 0.31 mmol) andDIEA (51 mg, 0.4 mmol) for 2 hours at 23° C. Ammonium hydroxide-30% byweight (2 mL) was added and stirred for a further 30 minutes. Thereaction was partitioned between EtOAc (8 mL) and water (3 mL). Theorganic layer was washed with water (3 mL), dried with MgSO₄, filteredand evaporated in vacuo. The crude reaction mixture was purified bypreparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 20% to 100%acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound as a 1:1 mixture of diastereomers. ¹H NMR(500 MHz, Chloroform-d₁) δ ppm 8.3 (m, 2H), 7.38-7.22 (m, 10H),6.34-6.18 (bs, 2H), 5.83-5.68 (bs, 2H), 5.52-5.41 (m, 2H), 4.06-3.95 (m,2H), 3.31-3.18 (m, 2H), 3.01-2.78 (m, 2H), 2.62-2.44 (m, 4H), 2.1-1.87(m, 24H), 1.56-1.53 (m, 6H), 1.47-1.43 (m, 6H); MS (APCI) m/z 424 (M+H).

Example 43E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide Example 43A Potassium;3-methyl-2-oxo-1-((1S)-1-phenylethyl)pyrrolidine-3-carboxylate

A solution of the product of Example 31B (0.075 gm, 0.4 mmol),(S)-1-phenylethylamine (58 mg, 0.47 mmol) and MP-triacetoxy borohydride(431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at 23° C. Thesolution was filtered and evaporated in vacuo. The resulting oil wastaken up in toluene (1.5 mL) and heated at 100° C. for 5 hours. Thesolvent was evaporated in vacuo and the residue taken in THF (1.2 mL)and stirred with KOTMS (77 mg, 0.6 mmol) at 23° C. for 12 hours. Thesolvent was evaporated in vacuo to provide Example 43A as a 1:1 mixtureof diastereomers.

Example 43BE-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide

A solution of the product of Example 43A (50 mg, 0.17 mmol), the productof Example 1C (52 mg, 0.21 mmol), TBTU (87 mg, 0.27 mmol) and DTEA (51mg, 0.4 mmol) in DMF (1.2 mL) was stirred at 23° C. for 2 hours. Thereaction was partitioned between EtOAc (8 ml) and water (4 ml). Theorganic layer was separated and washed twice with water (4 mL each),dried with MgSO₄, filtered and evaporated in vacuo. The resulting oilwas taken in THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) at 23°C. for 12 hours. The solvent was evaporated in vacuo. The resultingsolid was taken in DMF (1 mL) and stirred with TBTU (98 mg, 0.31 mmol)and DTEA (51 mg, 0.4 mmol) at 23° C. for 2 hours. Ammonium hydroxide-30%by weight (2 mL) was added and stirred for a further 30 minutes. Thereaction was partitioned between EtOAc (8 mL) and water (3 mL). Theorganic layer was washed with water (3 mL), dried with MgSO₄, filtered,and evaporated in vacuo. The crude reaction mixture was purified bypreparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 20% to 100%acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound as a 1:1 mixture of diastereomers. ¹H NMR(500 MHz, Chloroform-d₁) δ ppm 8.29 (m, 2H), 7.34-7.18 (m, 10H),6.30-6.14 (bs, 2H), 5.79-5.66 (bs, 2H), 5.48-5.37 (m, 2H), 4.06-3.95 (m,2H), 3.31-3.18 (m, 2H), 3.01-2.78 (m, 2H), 2.62-2.44 (m, 4H), 2.1-1.87(m, 24H), 1.56-1.53 (m, 6H), 1.47-1.43 (m, 6H); MS (APCI) m/z 424 (M+H).

Example 44E-4-{[2-methyl-2-(1,3-thiazol-2-yl)propanoyl]amino}adamantane-1-carboxamideExample 44A Diethyl2-(3-(ethoxycarbonyl)-2,3-dihydrothiazol-2-yl)malonate

Ethyl chloroformate (6.46 ml, 67.8 mmoles) was added dropwise to astirred solution of thiazole (5.0 g, 58.7 mmoles) in tetrahydrofuran(113.0 ml) at about 0° C. under a nitrogen atmosphere. After about 1hour, a freshly prepared solution of lithio diethylmalonate (To asolution of diethylmalonate (10.3 ml, 67.8 mmoles) in tetrahydrofuran(17.0 ml) was added dropwise a 1 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (67.8 ml, 67.8 mmoles) andthe mixture was stirred at 23° C. for about 10 min) was added viacannula and the mixture was stirred at room temperature for about 18hours. The mixture was diluted with diethyl ether (60.0 ml), was washedwith saturated aqueous ammonium chloride (140.0 ml) and brine (120.0ml). The organic layer was dried over MgSO₄, filtered, concentrated invacuum and the crude product was purified by flash column chromatographyon silica gel using hexanes/ethyl acetate (2:1) as the mobile phase toprovide the title compound.

Example 44B Diethyl 2-(thiazol-2(3H)-ylidene)malonate

To a solution of the product of Example 44A (12.9 g, 40.7 mmoles) indichloromethane (100.0 ml) was added tetrachloro-1,2-benzoquinone (10.0g, 40.7 mmoles) in portions at about 0° C., such that the mixture alwayshad time to decolorize to a yellow-orange color. The mixture was thenstirred for about 1 hour at 0° C. and was then washed with saturatedaqueous sodium bicarbonate solution (200.0 ml) and brine (100.0 ml). Theorganic layer was dried over MgSO₄, filtered, concentrated in vacuum andthe crude product was purified by flash column chromatography on silicagel using hexanes/ethyl acetate (2:1) as the mobile phase to provide thetitle compound.

Example 44C Ethyl 2-(thiazol-2-yl)acetate

A solution of the product of Example 44B (2.8 g, 11.5 mmoles), sodiumchloride (1.3 g, 22.9 mmoles) and water (0.4 ml, 22.9 mmoles) indimethyl sulfoxide (48.0 ml) was stirred at about 180° C. for about 30min. The mixture was cooled, diluted with water (100.0 ml) and wasextracted twice with (1:1) ethyl acetate/diethyl ether (80.0 ml each).The combined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated in vacuum. The crude product was purified byflash column chromatography on silica gel using hexanes/ethyl acetate(2:1) as the mobile phase to provide the title compound.

Example 44D Ethyl 2-methyl-2-(thiazol-2-yl)propanoate

The title compound was prepared according to the method of Example 22Asubstituting the product of Example 44C for ethyl 4-bromophenylacetate.

Example 44E 2-Methyl-2-(thiazol-2-yl)propanoic acid

The title compound was prepared according to the method of Example 22Bsubstituting the product of Example 44D for the product of Example 22A.

Example 44FE-4-(2-Methyl-2-thiazol-2-yl-propionylamino)-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22Csubstituting the product of Example 44E for the product of Example 22B.

Example 44GE-4-(2-Methyl-2-thiazol-2-yl-propionylamino)-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 23Dsubstituting the product of Example 44F for the product of Example 23C.

Example 44HE-4-(2-Methyl-2-thiazol-2-yl-propionylamino)-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method of Example 35Csubstituting the product of Example 44G for the product of Example 35B.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.86 (d, J=3.30 Hz, 1H), 7.71 (d, J=3.29Hz, 1H), 7.42 (d, J=7.26 Hz, 1H), 6.94-6.97 (bs, 1H), 6.67-6.69 (bs,1H), 3.72-3.77 (m, 1H), 1.82-1.88 (m, 3H), 1.75-1.82 (m, 4H), 1.71-1.74(m, 2H), 1.62 (s, 6H), 1.57-1.64 (m, 2H), 1.39-1.47 (m, 2H); MS (ESI+)m/z 348 (M+H)⁺.

Example 45E-4-(aminocarbonyl)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpiperidine-3-carboxamideExample 45A Piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethylester

To a room temperature solution of 4.05 g (25.8 mmoles) of ethylnipecotate and 4.33 g (51.5 mmoles) of NaHCO₃ in water (26 mL) was addedbenzyl chloroformate (4.1 mL, 28.3 mmol). The reaction mixture wasstirred at 23° C. under an atmosphere of N₂ overnight. The crudeproducts were diluted with water, extracted with Et₂O, washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography employing a solventgradient (hexane→70:30 hexane:EtOAc) to yield the title compound as aclear colorless oil.

Example 45B 3-Methyl-piperidine-1,3-dicarboxylic acid 1-benzyl ester

To a −78° C. solution of the product of Example 45A (6.0 g, 20.6 mmoles)in THF (50 mL) was added a solution of lithium bis(trimethylsilyl)amide(1.0 M in THF, 22.7 mmoles). After 35 min, iodomethane (1.4 mL, 22.7mmoles) was added and the reaction was slowly warmed to room temperatureand stirred overnight. The reaction was quenched with aqueous sat.ammonium chloride and extracted with Et₂O. The organic layer was thenrinsed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatographyemploying a solvent gradient (hexane→65:35 hexane:EtOAc). The resultingester was hydrolyzed overnight at room temperature in THF (15 mL), H₂O(10 mL), and EtOH (15 mL) with NaOH (2.5 g). The solution wasconcentrated under vacuum; the residue was dissolved in saturatedammonium chloride; and, the solution was extracted with ethyl acetate(3×). The combined ethyl acetate extracts were dried over sodiumsulfate, filtered, and concentrated under vacuum to yield the titlecompound as a white solid.

Example 45CN-[E-4-(carbomethoxy)-2-adamantyl]-1-(4-benzyloxycarbonyl)-3-methylpiperidine-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 7, substituting the product of Example 45B for2-phenylisobutyric acid and substituting the product of Example 1C for2-adamantanamine hydrochloride.

Example 45DN-[E-4-(carbomethoxy)-2-adamantyl]-1-3-methylpiperidine-3-carboxamide

A solution of the product of Example 45C (0.62 g, 1.32 mmoles) and 10%palladium on carbon (60 mg) in EtOAc (20 mL) was exposed to hydrogen (60psi) at room temperature for 6 hours. The reaction was incomplete soEtOH was added and the reaction continued for an additional 8 h. Thecrude product was then filtered away from the catalyst using methanoland isolated after concentration in vacuo to provide the title compound.

Example 45EE-4-(carbomethoxy)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpiperidine-3-carboxamide

To a solution of the product of Example 45D (100 mg, 0.3 mmoles) and4-chlorobenzaldehyde in dichloroethane (0.75 mL) and acetic acid (0.07mL, 1.2 mmoles) was added sodium triacetoxyborohydride (127 mg, 0.6mmoles). The resulting reaction mixture was stirred at room temperatureovernight. The reaction was quenched with sat. aqueous NH₄Cl andextracted with EtOAc. The organic layer was then rinsed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo to provide acrude sample of the title compound.

Example 45FE-4-(aminocarbonyl)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpiperidine-3-carboxamide

The crude product from Example 45E was hydrolyzed with an excess of NaOHat room temperature in a solution of water, EtOH, and tetrahydrofuranfor 16 hours. The reaction was quenched with sat. aqueous NH₄Cl andextracted with EtOAc. The organic layer was then rinsed with brine,dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue,EDCI (80 mg, 0.42 mmoles), and 1-hydroxybenzotriazole hydrate (56.5 mg,0.42 mmoles) were dissolved in DMF (0.75 mL) and stirred for 30 min atroom temperature. Concentrated NH₄OH (0.75 mL) was then added andstirring was continued overnight. The reaction was quenched with sat.aqueous NH₄Cl and extracted with EtOAc. The organic layer was thenwashed with water (2×), rinsed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo. The product was purified by reverse phasepreparative HPLC (acetonitrile: 10 mM NH₄OAc in H₂O on a YMC prep ODS-Acolumn) to provide the title compound. ¹H NMR (500 MHz, Chloroform-d₁) δppm 8.74-8.79 (m, 1H), 7.28-7.32 (m, 2H), 7.18-7.21 (m, 2H), 5.65-5.69(bs, 1H), 5.55-5.59 (bs, 1H), 4.04-4.07 (m, 1H), 3.56 (d, J=12.82 Hz,1H), 3.43 (d, J=12.82 Hz, 1H), 3.00-3.05 (m, 1H), 2.93-2.98 (m, 1H),2.08-2.13 (m, 1H), 2.00-2.05 (m, 1H), 1.93-2.00 (m, 6H), 1.90-1.94 (m,2H), 1.83-1.90 (m, 1H), 1.76-1.82 (m, 1H), 1.69-1.74 (m, 1H), 1.61-1.69(m, 1H), 1.52-1.63 (m, 4H), 1.12 (s, 3H), 1.06-1.15 (m, 1H); MS (ESI+)m/z 444 (M+H)⁺.

Example 46E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamideExample 46A 2-(4-Hydroxyphenyl)-proprionic acid methyl ester

The title compound was prepared according to the method as described inExample 36A substituting 2-(4-hydroxyphenyl)-proprionic acid for3-bromophenylacetic acid.

Example 46B 2-(4-Allyloxyphenyl)-proprionic acid methyl ester

A solution of the product of Example 46A (2.6 g, 12 mmol) in anhydrousdimethylformamide (20 mL) was treated with potassium carbonate (3.3 g,24 mmol) and allyl bromide (1.2 mL, 13 mmol), and reaction heated for 16hours at 80° C. Reaction mixture cooled and diluted with ethyl acetate.Mixture washed with water and brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Residue purified by normal phaseHPLC on silica gel eluting with 3% ethyl acetate/hexane to provide thetitle compound.

Example 46C 2-(4-Allyloxyphenyl)-2-methylproprionic acid methyl ester

A 0° C. solution of the product of Example 46B (1.9 g, 8.6 mmol) inanhydrous dimethylformamide (10 mL) was treated portion-wise with 60%sodium hydride (410 mg, 10 mmol) in mineral oil. The reaction mixturewas stirred twenty minutes at 0° C., and methyl iodide (1.4 mL, 22 mmol)was then added. Ice bath was removed, and reaction mixture stirred 16hours at room temperature. Reaction mixture quenched with saturatedammonium chloride, and product extracted with ethyl acetate (2×). Thecombined extracts were washed with water and brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. Residue purified bynormal phase HPLC on silica gel eluting with 3% ethyl acetate/hexane toprovide the title compound.

Example 46D 2-(4-Allyloxyphenyl)-2-methylproprionic acid

The title compound was prepared according to the method as described inExample 27B, substituting the product of Example 46C for the product ofExample 27A.

Example 46EE-4-[2-(4-Allyloxyphenyl)-2-methylpropionylamino]-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method as described inExample 27A, substituting the product of Example 46D for1-(4-methoxyphenyl)-1-cyclopentanecarboxylic acid.

Example 46FE-4-[2-(4-Hydroxyphenyl)-2-methylpropionylamino]-adamantane-1-carboxylicacid methyl ester

A 0° C. solution of the product of Example 46E (1.4 g, 3.4 mmol) andtetrakis(triphenylphosphine)palladium (390 mg, 0.34 mmol) in anhydrousmethylene chloride (10 mL) was treated with phenyl silane (0.84 mL, 6.8mmol). Reaction stirred ten minutes at 0° C. and two hours at roomtemperature. Reaction diluted with methylene chloride, washed withbrine, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. Residue purified by normal phase HPLC on silica gel elutingwith 30-40% ethyl acetate/hexane to provide the title compound.

Example 46GE-4-[2-(4-Hydroxyphenyl)-2-methylpropionylamino]-adamantane-1-carboxylicacid

The title compound was prepared according to the method as described inExample 27B substituting the product of Example 46F for the product ofExample 27A.

Example 46HE-4-[2-(4-Hydroxyphenyl)-2-methylpropionylamino]-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method as described inExample 27C, substituting the product of Example 46G for the product ofExample 27B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.24-9.38 (bs, 1H),7.15-7.17 (m, 2H), 6.95-6.97 (bs, 1H), 6.69-6.74 (m, 3H), 6.69-6.70 (m,1H), 6.03 (d, J=7.16 Hz, 1H), 3.69-3.73 (m, 1H), 1.80-1.83 (m, 2H),1.73-1.79 (m, 4H), 1.67-1.69 (m, 2H), 1.44-1.50 (m, 2H), 1.43 (s, 6H),1.30-1.36 (m, 2H); MS (ESI+) m/z 357 (M+H)⁺.

Example 47E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopiperidine-3-carboxamideExample 47A Potassium; 1-benzyl-3-methyl-2-oxo-piperidine-3-carboxylate

A solution of the product of Example 30B (0.075 gm, 0.37 mmol),benzylamine (47 mg, 0.44 mmol) and MP-triacetoxy borohydride (420 mg,0.92 mmol) in THF (2 mL) was stirred for 12 hours at 23° C. The solutionwas filtered and evaporated in vacuo. The resulting oil was taken up inTHF (1.2 mL) and stirred with KOTMS (71 mg, 0.55 mmol) for 12 hours at23° C. The solvent was evaporated in vacuo to provide Example 47A.

Example 47BE-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopiperidine-3-carboxamide

A solution of the product of Example 47A (50 mg, 0.17 mmol), the productof Example 1C (49 mg, 0.2 mmol), TBTU (87 mg, 0.27 mmol) and DIEA (54mg, 0.42 mmol) in DMF (1.2 mL) was stirred for 2 hours at 23° C. Thereaction was partitioned between EtOAc (8 ml) and water (4 ml). Theorganic layer was separated and washed twice with water (4 mL each),dried with MgSO₄, filtered and evaporated in vacuo. The resulting oilwas taken in THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) for 12hours at 23° C. The solvent was evaporated in vacuo. The resulting solidwas taken in DMF (1 mL) and stirred with TBTU (96 mg, 0.3 mmol) and DIEA(53 mg, 0.42 mmol) at 23° C. for 2 hours. Ammonium hydroxide-30% byweight (2 mL) was added and stirred for a further 30 minutes. Thereaction was partitioned between EtOAc (8 mL) and water (3 mL). Theorganic layer was washed with water (3 mL), dried with MgSO4 andevaporated in vacuo. The crude reaction mixture was purified bypreparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 um particle size) using a gradient of 20% to 100%acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40 mL/min.to provide the title compound. ¹H NMR (500 MHz, Chloroform-d₁) δ ppm8.17 (d, J=7.93 Hz, 1H), 7.27-7.34 (m, 3H), 7.21-7.24 (m, 2H), 6.12-6.17(bs, 1H), 5.68-5.83 (m, 1H), 4.95 (d, J=14.58 Hz, 1H), 4.29 (d, J=14.59Hz, 1H), 3.97-4.02 (m, 1H), 3.24-3.35 (m, 2H), 2.65 (ddd, J=13.31, 5.72,2.61 Hz, 1H), 2.09-2.11 (m, 1H), 1.96-2.05 (m, 6H), 1.85-1.90 (m, 3H),1.64-1.83 (m, 4H), 1.55-1.63 (m, 2H), 1.54 (s, 3H); MS (APCI) m/z 424(M+H).

Example 48E-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxamideExample 48A Methyl 2-(4-phenoxyphenyl)acetate

To a solution of 4-phenoxyphenylacetic acid (1.0 g, 4.38 mmoles) inmethanol (5.0 ml) was added concentrated sulfuric acid (0.05 ml, 0.88mmoles) and the mixture was heated to reflux for about 5 hours. Themixture was cooled and concentrated under reduced pressure. To theresidue was added a saturated aqueous solution of sodium bicarbonate(20.0 ml) and the mixture was extracted with ethyl acetate. The combinedorganic extracts were washed with water and brine, dried over MgSO₄,filtered and evaporated to dryness to afford the title compound.

Example 48B Methyl 2-methyl-2-(4-phenoxyphenyl)propanoate

The title compound was prepared according to the method of Example 22Asubstituting the product of Example 48A for ethyl-4-bromophenyl acetate.

Example 48C 2-Methyl-2-(4-phenoxyphenyl)propanoic acid

The title compound was prepared according to the method of Example 22B,substituting the product of Example 48B for the product of Example 22A.

Example 48DE-4-[2-Methyl-2-(4-phenoxy-phenyl)-propionylamino]-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22C,substituting the product of Example 48C for the product of Example 22B.

Example 48EE-4-[2-Methyl-2-(4-phenoxy-phenyl)-pronionylamino]-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 23D,substituting the product of Example 48D for the product of Example 23C.

Example 48FE-4-[2-Methyl-2-(4-phenoxy-phenyl)-propionylamino]-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method of Example 35C,substituting the product of Example 48E for the product of Example 35B.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34-7.41 (m, 4H), 7.10-7.15 (m, 1H),6.93-7.01 (m, 5H), 6.66-6.68 (bs, 1H), 6.22 (d, J=6.94 Hz, 1H),3.72-3.77 (m, 1H), 1.85-1.88 (m, 2H), 1.73-1.84 (m, 5H), 1.70-1.71 (m,2H), 1.53-1.59 (m, 2H), 1.49 (s, 6H), 1.33-1.38 (m, 2H); MS (ESI+) m/z433 (M+H)⁺.

Example 49E-4-{[2-(1-benzothien-3-yl)-2-methylpropanoyl]amino}adamantine-1-carboxamideExample 49A Methyl 2-(benzo[b]thiophen-3-yl)acetate

The title compound was prepared according to the method of Example 48Asubstituting benzo[b]thiophene-3-acetic acid for 4-phenoxyphenylaceticacid.

Example 49B Methyl 2-(benzo[b]thiophen-3-yl)-2-methylpropanoate

The title compound was prepared according to the method of Example 22Asubstituting the product of Example 48A for ethyl-4-bromophenylacetate.

Example 49C 2-(Benzo[b]thiophen-3-yl)-2-methylpropanoic acid

The title compound was prepared according to the method of Example 22Bsubstituting the product of Example 49B for the product of Example 22A.

Example 49D4-(2-Benzo[b]thiophen-3-yl-2-methyl-propionylamino)-adamantane-1-carboxylicacid methyl ester

The title compound was prepared according to the method of Example 22C,substituting the product of Example 49C for the product of Example 22B.

Example 49E4-(2-Benzo[b]thiophen-3-yl-2-methyl-propionylamino)-adamantane-1-carboxylicacid

The title compound was prepared according to the method of Example 23Dsubstituting the product of Example 49D for the product of Example 23C.

Example 49F4-(2-Benzo[b]thiophen-3-yl-2-methyl-propionylamino)-adamantane-1-carboxylicacid amide

The title compound was prepared according to the method of Example 35Csubstituting the product of Example 49E for the product of Example 35B.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.97 (s, 1H), 7.64-7.66 (m, 2H),7.31-7.36 (m, 2H), 6.89-6.92 (bs, 1H), 6.63-6.66 (bs, 1H), 6.13 (d,J=7.21 Hz, 1H), 3.71-3.76 (m, 1H), 1.66-1.79 (m, 1.60 (s, 6H), 1.55-1.63(m, 3H), 1.07-1.18 (m, 4H); MS (ESI+) m/z 397 (M+H)⁺.

Example 50E-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamideExample 50A Potassium; 2-(5-fluoro-pyridin-2-yl)-2-methyl-propionate

A solution of 2-bromo-5-fluoropyridine (315 mg, 1.8 mmol), methyltrimethylsilyl dimethylketene acetal (0.378 mg, 2.17 mmol), zincfluoride (112 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0)(20 mg, 0.021 mmol) and tri-t-butylphosphine-10 wt % in hexane (172 mg,0.084 mmol) in Argon degassed DMF (1.5 mL) was stirred at 90° C. for 12hours. The reaction was taken up in EtOAc (25 mL) and washed with water(15 mL) followed by brine (15 mL). The organic layer was dried withMgSO₄, filtered, and evaporated in vacuo. The crude product was purifiedby flash chromatography (hexane/EtOAc 100:0 to 80:20) to give the methylester of Example 50A. A solution of the corresponding methyl ester (144mg, 0.73 mmol), potassium trimethylsilanolate (KOTMS) (140 mg, 1.1 mmol)in THF (2 mL) was stirred for 12 hours at 23° C. Methyl t-butyl ether(MTBE) 8 mL was added to the solution and Example 50A was isolated byfiltration.

Example 50BE-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide

A solution of the product of Example 50A (30 mg, 0.15 mmol), the productof Example 1C (45 mg, 0.18 mmol), TBTU (77 mg, 0.24 mmol) and DIEA (47mg, 0.37 mmol) in DMF (1.2 mL) was stirred at 23° C. for 3 hrs. Thereaction was diluted with EtOAc (10 mL) and washed twice with water (6mL) and brine (6 mL). The organic layer was dried with MgSO₄, filtered,and evaporated in vacuo. The residue was taken in THF (1 mL) and stirredwith KOTMS (29 mg, 0.22 mmol) for 12 hours at 23° C. The solvent wasevaporated in vacuo. The residue solid was taken in DMF (1 mL) and addedTBTU (86 mg, 0.27 mmol), DIEA (47 mg, 0.37 mmol) and stirred at 23° C.for 2 hours. Ammonium hydroxide-30% by weight (2 mL) was added andstirred for a further 30 minutes. The reaction was partitioned betweenEtOAc (8 mL) and water (3 mL). The organic layer was washed with water(3 mL), dried with MgSO₄, filtered and evaporated in vacuo. The crudereaction mixture was purified by preparative reverse phase HPLC on aWaters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using agradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at aflow rate of 40 mL/min. to provide the title compound as thetrifluoroacetic acid salt. ¹H NMR (500 MHz, Chloroform-d₁) δ ppm8.51-8.55 (m, 1H), 7.58-7.64 (m, 1H), 7.50-7.55 (m, 2H), 7.42-7.48 (bs,1H), 6.83-7.12 (bs, 1H), 6.00-6.07 (bs, 1H), 3.93-3.98 (m, 1H),2.02-2.07 (m, 3H), 1.94-1.97 (m, 4H), 1.87-1.90 (m, 2H), 1.70 (s, 6H),1.66-1.72 (m, 2H), 1.56-1.62 (m, 2H); MS (APCI) m/z 360 (M+H).

Example 51E-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamideExample 51A Potassium; 2-methyl-2-quinoxalin-2-yl-propionate

A solution of 2-chloroquinoxaline (295 mg, 1.8 mmol), methyltrimethylsilyl dimethylketene acetal (0.378 mg, 2.17 mmol), zincfluoride (112 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0)(20 mg, 0.021 mmol) and tri-t-butylphosphine-10 wt % in hexane (172 mg,0.084 mmol) in Argon degassed DMF (1.5 mL) was stirred at 90° C. for 12hours. The reaction was taken up in EtOAc (25 mL) and washed with water(15 mL) followed by brine (15 mL). The organic layer was dried withMgSO₄, filtered and evaporated in vacuo. The crude product was purifiedby flash chromatography (hexane/EtOAc 100:0 to 80:20) to give the methylester of Example 51A. A solution of the corresponding methyl ester (168mg, 0.73 mmol), potassium trimethylsilanolate (KOTMS) (140 mg, 1.1 mmol)in THF (2 mL) was stirred at 23° C. for 12 hours. Methyl t-butyl ether(MTBE) 8 mL was added to the solution and Example 51A was isolated byfiltration.

Example 51BE-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamide

A solution of the product of Example 51A (30 mg, 0.12 mmol), the productof Example 1C (35 mg, 0.14 mmol), TBTU (61 mg, 0.19 mmol) and DIEA (38mg, 0.3 mmol) in DMF (1.2 mL) was stirred at 23° C. for 3 hrs. Thereaction was diluted with EtOAc (10 mL) and washed twice with water (6mL) and brine (6 mL). The organic layer was dried with MgSO₄, filteredand evaporated in vacuo. The residue was taken in THF (1 mL) and stirredwith KOTMS (23 mg, 0.18 mmol) at 23° C. for 12 hours. The solvent wasevaporated in vacuo. The residue solid was taken in DMF (1 mL) and addedTBTU (69 mg, 0.22 mmol), DIEA (38 mg, 0.3 mmol) and stirred at 23° C.for 2 hours. Ammonium hydroxide-30% by weight (2 mL) was added andstirred for a further 30 minutes. The reaction was partitioned betweenEtOAc (8 mL) and water (3 mL). The organic layer was washed with water(3 mL), dried with MgSO₄, filtered, and evaporated in vacuo. The crudereaction mixture was purified by preparative reverse phase HPLC on aWaters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using agradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at aflow rate of 40 mL/min. to provide the title compound as thetrifluoroacetic acid salt. NMR (400 MHz, Chloroform-d₁) δ ppm 9.03 (s,1H), 8.12-8.16 (m, 1H), 8.04-8.08 (m, 1H), 7.76-7.85 (m, 2H), 7.33-7.38(m, 1H), 6.28-6.41 (m, 1H), 5.69-5.82 (m, 1H), 3.91-4.05 (m, 1H),1.96-2.04 (m, 4H), 1.89-1.97 (m, 4H), 1.84-1.88 (m, 2H), 1.83 (s, 6H),1.62-1.69 (m, 2H), 1.52-1.59 (m, 2H); MS (APCI) m/z 393 (M+H).

Biological Data

Measurement of Inhibition Constants:

The ability of test compounds to inhibit human 11β-HSD-1 enzymaticactivity in vitro was evaluated in a Scintillation Proximity Assay(SPA). Tritiated-cortisone substrate, NADPH cofactor and titratedcompound were incubated with truncated human 11β-HSD-1 enzyme (24-287AA)at room temperature to allow the conversion to cortisol to occur. Thereaction was stopped by adding a non-specific 11β-HSD inhibitor,18β-glycyrrhetinic acid. The tritiated cortisol was captured by amixture of an anti-cortisol monoclonal antibody and SPA beads coatedwith anti-mouse antibodies. The reaction plate was shaken at roomtemperature and the radioactivity bound to SPA beads was then measuredon a β-scintillation counter. The 11-βHSD-1 assay was carried out in96-well microtiter plates in a total volume of 220 μl. To start theassay, 188 μl of master mix which contained 17.5 nM ³H-cortisone, 157.5nM cortisone and 181 mM NADPH was added to the wells. In order to drivethe reaction in the forward direction, 1 mM G-6-P was also added. Solidcompound was dissolved in DMSO to make a 10 mM stock followed by asubsequent 10-fold dilution with 3% DMSO in Tris/EDTA buffer (pH 7.4).22 μl of titrated compounds was then added in triplicate to thesubstrate. Reactions were initiated by the addition of 10 μl of 0.1mg/ml E. coli lysates overexpressing 11β-HSD-1 enzyme. After shaking andincubating plates for 30 minutes at room temperature, reactions werestopped by adding 10 μl of 1 mM glycyrrhetinic acid. The product,tritiated cortisol, was captured by adding 10 μl of 1 mM monoclonalanti-cortisol antibodies and 100 μl SPA beads coated with anti-mouseantibodies. After shaking for 30 minutes, plates were read on a liquidscintillation counter Topcount. Percent inhibition was calculated basedon the background and the maximal signal. Wells that contained substratewithout compound or enzyme were used as the background, while the wellsthat contained substrate and enzyme without any compound were consideredas maximal signal. Percent of inhibition of each compound was calculatedrelative to the maximal signal and IC₅₀ curves were generated. Thisassay was applied to 11β-HSD-2 as well, whereby tritiated cortisol andNAD⁺ were used as substrate and cofactor, respectively.

Compounds of the present invention are active in the 11-βHSD-1 assaydescribed above and show selectivity for human 11-β-HSD-1 over human11-β-HSD-2, as indicated in Table 1.

TABLE 1 11-β-HSD-1 and 11-β-HSD-2 activity for representative compounds.Compound 11-β-HSD-1 IC₅₀ (nM) 11-β-HSD-2 IC₅₀ (nM) A (Example 1)43 >10,000 B (Example 2) 102 C (Example 3) 82 >10,000 D (Example 4) 24 G(Example 9) 59 7,400 H (Example 10) 33 >30,000 I (Example 11) 35 12,000J (Example 12) 33 30,000 K (Example 13) 43 16,000 L (Example 14) 2516,000 M (Example 15) 30 >30,000 N (Example 16) 31 >30,000 O (Example17) 38 16,000 P (Example 18) 38 >30,000 Q (Example 19) 36 16,000 R(Example 20) 27 21,000 S (Example 21) 37 15,000 T (Example 22)31 >30,000 U (Example 23) 16 12,000 V (Example 24) 19 15,000 W (Example25) 23 >30,000 X (Example 26) 104 >30,000 Y (Example 27) 18 13,000 Z(Example 28) 21 23,000 AA (Example 30) 15 15,000 BB (Example 31) 2630,000 CC (Example 32) 23 12,000 DD (Example 33) 23 6,300 EE (Example34) 29 10,000 FF (Example 35) 28 >100,000 GG (Example 36) 17 9,300 HH(Example 37) 44 40,000 II (Example 38) 62 44,000 JJ (Example 39) 9560,000

The data in Table 1 demonstrates that compounds of formula (I) areactive in the human 11β-HSD-1 enzymatic SPA assay described above andthe tested compounds show selectivity for 11β-HSD-1 over 11β-HSD-2. The11β-HSD-1 inhibitors of this invention generally have an inhibitionconstant IC₅₀ of less than 600 nM and preferably less than 50 nM. Thecompounds preferably are selective, having an inhibition constant IC₅₀against 11β-HSD-2 greater than 1000 nM and preferably greater than10,000 nM. Generally, the IC₅₀ ratio for 11β-HSD-2 to 11β-HSD-1 of acompound is at least 10 or greater and preferably 100 or greater.

Metabolic Stability

Incubation Conditions:

Metabolic stability screen: each substrate (10 μM) was incubated withmicrosomal protein (0.1-0.5 mg/ml) in 50 mM potassium phosphate buffer(pH 7.4) in 48-Well plate. The enzyme reaction was initiated by theaddition of 1 mM NADPH, then incubated at 37° C. in a Form a Scientificincubator (Marietta, Ohio, USA) with gentle shaking. The reactions werequenched by the addition of 800 μl of ACN/MeOH (1:1, v/v), containing0.5 μM of internal standard (IS), after 30 min incubation. Samples werethen filtered by using Captiva 96-Well Filtration (Varian, Lake Forest,Calif., USA) and analyzed by LC/MS (mass spectrometry). Liver microsomalincubations were conducted in duplicate.

LC/MS Analysis:

The parent remaining in the incubation mixture was determined by LC/MS.The LC/MS system consisted of an Agilent 1100 series (AgilentTechnologies, Waldbronn, Germany) and API 2000 (MDS SCIEX, Ontario,Canada). A Luna C8(2) (50×2.0 mm, particle size 3 μm, Phenomenex,Torrance, Calif., USA) was used to quantify each compound at ambienttemperature. The mobile phase consisted of (A): 10 mM NH₄AC (pH 3.3) and(B): 100% ACN and was delivered at a flow rate of 0.2 ml/min. Elutionwas achieved using a linear gradient of 0-100% B over 3 min, then held100% B for 4 min and returned to 100% A in 1 min. The column wasequilibrated for 7 min before the next injection.

The peak area ratios (each substrate over IS) at each incubation timewere expressed as the percentage of the ratios (each substrate over IS)of the control samples (0 min incubation). The parent remaining in theincubation mixture was expressed as the percentage of the values at 0min incubation. The percentage turnover is calculated using thefollowing equation (% turnover=100% turnover−% parent remaining) and isrecorded as the percentage turnover in the Table 2.

TABLE 2 Microsomal metabolic stability. Human Liver Microsomal MouseLiver Microsomal Compound Turnover (%) Turnover (%) A 5 5 B 2 0 C 0 0 D10 E 83 F 62

Compounds A, B, C and D contain a substituted adamantane, whereas theadamantane ring of Compounds E and F is unsubstituted. The microsomal,metabolic, stability data in Table 2 demonstrates that substitutedadamantane compounds of the present invention may exhibit an increase inmetabolic stability compared to unsubstituted adamantane compounds whichmay lead to longer in vivo half lives and pharmacokinetic advantagesover unsubstituted adamantanes.

Selective 11β-HSD1 Inhibitors Enhance Memory Consolidation in Mice After2-Week Food-in-Diet Dosing

Episodic memory is a type of long-term memory that requires one exposurefor memory formation to occur. Patients with Alzheimer's disease sufferfrom episodic memory dysfunction, among other cognitive deficits. Inaddition, studies indicate that patients with a genetic risk forAlzheimer's disease have early deficits in episodic memory and executivefunction (Ringman, J. Geriatr. Psychiatry Neurology, 2005, 18:228-233).

The 24-hour inhibitory avoidance task in mice is a measure of one-triallearning and memory consolidation in response to a discrete aversiveevent (foot-shock). Mice are first placed in an illuminated compartmentof a two-compartment apparatus. Mice will naturally step through into anadjoining dark compartment, which they prefer. When the mice enter thedark they receive a mild foot-shock. To assess memory, mice are tested24 hours later and the length of time the animal refrains from enteringthe dark compartment is recorded (higher latencies indicate improvedmemory for the aversive event).

Male CD-1 mice were obtained from Charles River, Wilmington, Mass. Micewere group-housed 10 per cage. The body weight upon arrival was 20-25 g.Food and water were available ad libitum except during experiments.Animals were acclimated to the animal facilities for a period of atleast one week prior to commencement of experiments. Animals were testedin the light phase of a 12-hour light: 12-hour dark schedule (lights on0600 hours).

Compound KK([2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylsulfonyl)-2-adamantyl]propanamide])was synthesized at Abbott Laboratories. Compound KK was administered viaa drug-in-diet administration (100 mg/kg/day in Western diet) or (10mg/kg/day in Western diet).

On the first day of testing (17 days after drug-in-diet was presented)mice were removed from the colony room in their home cage, brought tothe testing room, and left undisturbed for 2 hours prior to testinginitiation. Following this habituation period, drug-in-diet mice weretested. Upon testing initiation, mice were placed one at a time into thelight (safe) compartment of a two-chambered apparatus (Gemini apparatus,San Diego Instruments, San Diego, Calif.), during which time theretractable door was closed. After 30 sec at the completion of theacclimation period the door between the light and dark compartments wasopened. Measurement of the training latency commenced at this point.This measure (training) provides some indication of general locomotoractivity. If a mouse has not crossed within 60 s the animal's data isexcluded from the analysis. After the mouse crossed into the darkchamber the door was lowered and inescapable footshock (0.13 mA, 1 secduration) was presented to the mouse after it completely entered thechamber and the door closed. The mouse was immediately removed from thechamber and returned to the home cage. 24-hours later the mouse wastested using methods identical to those on the training day, exceptwithout being dosed and without shock presentation. The latency to enterthe dark chamber was recorded and was the dependent variable measuredfor assessing memory retention (latency is defined as entry of the wholemouse; all 4 paws on the grids in the dark side, plus the tail in thechamber for 5 sec; 180 sec is maximum latency). Data were analyzed usingMann Whitney U comparisons. P<0.05 was regarded as significant. Asillustrated in FIG. 1, there was a significant improvement in memoryretention following the administration of Compound KK at both dosescompared to the response of vehicle control mice.

A Selective 11β-HSD1 Inhibitor Enhances Phosphorylated CREB, aBiochemical Marker of Cognitive Enhancement, in Mice After 2-WeekFood-in-Diet Dosing

In vivo signaling studies were conducted to examine the biochemicalpathways that may be mechanistically involved in the cognitive efficacyassociated with Compound KK. An important signaling process that servesas a biochemical correlate of synaptic plasticity underlying learningand memory is the phosphorylation of CREB (c-AMP-response elementbinding protein), a transcription factor critical to long-term memory.To investigate the effects of Compound KK on CREB phosphorylation, CD1mice treated and tested (data presented in FIG. 1) were given a 24-hourrest after testing before immunohistochemical procedures commenced.

Male CD-1 mice were obtained from Charles River, Wilmington, Mass. Micewere group-housed 10 per cage. The body weight upon arrival was 20-25 g.Food and water were available ad libitum except during experiments.Animals were acclimated to the animal facilities for a period of atleast one week prior to commencement of experiments. Animals were testedin the light phase of a 12-hour light: 12-hour dark schedule (lights on0600 hours).

Compound KK was administered via a drug-in-diet administration (100mg/kg/day in Western diet) or (10 mg/kg/day in Western diet). 18-daysafter receiving Compound KK food-in-diet (10 and 100 mg/kg/day) ratswere anesthetized and perfused through the aorta with normal salinefollowed by 10% formalin. Following perfusion, brains were removed andpostfixed in 20% sucrose-PBS (phosphate buffered saline) overnight andsubsequently cut on a cryostat (40 μm coronal sections) and collected asfree-floating sections in PBS. Sections were then immunostained for Fosprotein using a 3-step ABC-peroxidase technique beginning with a 30-minincubation with blocking serum. Sections were next incubated withanti-phsopho-CREB (rabbit IgG, 1:1000, Cell signaling) antibodies for 48hrs at 4 degrees C., washed with PBS and incubated for 1-hr with eitherbiotinylated secondary anti-sheep or anti-mouse antibody (Ab) solution(1:200). Finally, sections were washed in PBS, incubated with ABCreagent (Vector) and then developed in a peroxidase substrate solution.The sections were mounted, coverslipped and examined and photographedwith a light microscope (Leica, DMRB). Immuno-reactivity (IR) wasquantified using an image analysis system (Leica, Quantimet 500) thatdetermined number and/or area of peroxidase substrate-positive stainedneurons from digitized photomicrographs according to a pixel gray levelempirically determined prior to analysis. Overall statisticalsignificance was determined using a one-way ANOVA, with Dunnett's posthoc analyses used to determine significance (p<0.05 was consideredsignificant). FIG. 2 shows the increase in phosphorylated CREB followingthe administration of Compound KK mg/kg/day.

Selective 11β-HSD1 Inhibitors Enhance Memory Consolidation in Mice AfterSubchronic Dosing

The 24-hour inhibitory avoidance model in mice was used to evaluate theeffects of Compound KK and Compound LL([N-{(E)-5-[(Z)-Amino(hydroxyimino)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide])following a subchronic (3 administration) dosing regimen.

Male CD-1 mice were obtained from Charles River, Wilmington, Mass. Micewere group-housed 10 per cage. The body weight upon arrival was 20-25 g.Food and water were available ad libitum except during experiments.Animals were acclimated to the animal facilities for a period of atleast one week prior to commencement of experiments. Animals were testedin the light phase of a 12-hour light: 12-hour dark schedule (lights on0600 hours).

Compound KK and Compound LL were synthesized at Abbott Laboratories.Compounds AA and BB were solubilized in a solution of 5% Tween80/water.Compound KK was administered in a cloudy, fine suspension, whileCompound LL was administered in a solution.

Mice were weighed and dosed BID (≈8 AM and 3 PM) PO with Compound AA (30mg/kg), or Compound LL (30 mg/kg) or vehicle the day before training. Ontraining day, mice were injected with Compound KK, Compound LL orvehicle one-hour PO before training. One hour following injection (startof training) mice were subjected to a training session in which theywere placed in a lighted compartment of a two-compartment chamber(Gemini apparatus, San Diego Instruments, San Diego, Calif.) with amanually operated gate separating the compartments. Following a 30second habituation period in the lighted compartment, the door to theadjacent dark compartment was opened. Once the mouse had completelytransferred, the door was closed and a 0.13 mA current was applied tothe grid floor for 1 s. The mouse was then immediately removed andreturned to the home cage. Twenty-four hours later mice were againtested in the same apparatus, except without shock, and the transferlatency from the lighted to the dark compartment recorded and used as anindex of memory for the punished response 24 hours earlier. The electricshock parameters of this test were established such that vehicle treatedmice would only have minimal retention of the conditioning trial, thusallowing a large window for improvement of the memory following drugtreatment. Data were analyzed using Mann Whitney U comparisons. P<0.05was regarded as significant.

As illustrated in FIG. 3, there was a significant improvement in memoryretention following the administration of both Compounds AA and BBcompared to the response of vehicle control mice.

A Selective 11β-HSD1 Inhibitor Enhances Short-Term Memory in Rats AfterSubchronic Dosing

Social memory and social cognition are impaired in disorders such asAlzheimer's disease and schizophrenia. One of the more commonly usedpreclinical models of social recognition memory is short-term socialrecognition in the rat, a model of short-term memory based on therecognition of a juvenile rat by an adult rat. When adult rats areallowed to interact with a juvenile rat for 5 min, the adult exhibitsbehaviors such as close following, grooming or sniffing the juvenile foras much as 40-50% of the duration of a 5 min trial. The juvenile rat isthen removed and reintroduced 120 min later, and interactive behavior ofthe adult rat is again monitored. If memory has been lost over theinterval between trials 1 and 2, the extent of interaction is equal(expressed as a ratio of investigation time of T1/T2) and the ratio willbe close to 1. However, if the adult remembers the juvenile, theinvestigation ratio declines. To test for non-specific effects, a noveljuvenile is introduced at 120 minutes instead of the familiar juvenile.If the ratio is less than 1, this indicates the drug is having effectsthat may not be specific to cognition.

Male Sprague Dawley rats from Charles Rivers (Portage, Mich., USA) wereused. Adults weighed 370-500 g, and juveniles weighed 70-120 g at thetime of testing. All animals were housed in a quiet room underconditions of 12 h lights on/12 h lights off (on at 06:00 am) in groupsof four with food and water available ad libitum. Studies were conductedbetween 08:00 h and 16:00 h, and treatment groups were arranged forequal representation of time of day. Compound MM([N-[(E)-5-Hydroxy-2-adamantyl]-2-{-4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}acetamide],30 mg/kg) was dissolved in PEG 400 using a warm sonicator bath. Compoundwas administered in solution in a volume of 1 mL/1 g body weight, p.o.

Rats were pre-dosed po at 24, 18 and 1 hour before first juvenile ratexposure with vehicle, or Compound MM (30 mg/kg). During testing, theadult rat was placed into the test cage. After 30 min, a juvenile ratwas placed into the test cage with the adult rat for 5 min. The time theadult spent exploring (sniffing, grooming, close following) the juvenileduring this test session was recorded, and defined as the firstinvestigation duration. The juvenile was then removed from the testcage, and placed into its home cage. Following a further 90 min, theadult was placed back into the same test chamber, for a second 30-minhabituation. Following this second habituation the same juvenile(familiar) was again placed into the test cage for a 5-min test session;the time spent exploring the juvenile during this test session wasdefined as the second investigation duration. Vehicle treated rats donot remember the familiar juvenile following this two hr delay. Datawere analyzed using a one-way analysis of variance. If there was asignificant effect, subsequent post hoc significance was determinedusing Dunnett's multiple comparison testing (p<0.05 was regarded assignificant).

As shown in FIG. 4, there was a significant improvement in short-termmemory retention following the administration of Compound MM compared tothe response of vehicle control rats.

Effects of 11βHSD-1 Inhibitor on Rat Wake EEG Power Spektrum and REMSleep Parameter

EEG of Fisher rats (n=8/group) with chronically implanted supracorticalEEG-electrodes were analyzed for an 8 h period. Intraindividualdrug-induced changes of power spectra were analyzed. For REM sleep thenumber of REM episodes, latency to first REM, and total REM time wasanalyzed. Compound MM (30 mg/kg; 3 times at 24, 26, and 0.1 hours beforemeasurement) significantly reduced the number of REM sleep episodes by16% (total sleep time by 10%); the corresponding REM time was reduced by23%. The latency to first REM significantly increased by 62% (See FIGS.5 a, 5 b and 5 c, respectively).

The observed effects on REM were in line with the effects ofantidepressants like SSRIs and TCAs. These effects differ from theprocognitive effects induced by inhibitors of ACh-esteras like donepeziland physostigmine.

Modulation of Cortical/Hippocampal Acetylcholine Serotonin Release by11β-HSD1 Inhibition

Microdialysis studies (resting or challenging conditions) in freelymoving, male Sprague Dawley rats (Janvier, 295-315 g, n=5-8/treatmentgroup) were performed using stereotactically instrumented microdialysisprobes (CMA/12-14-2): mPFC, hippocampus. Aliquots of the samemicrodialysate fractions (6 before, and 9-12 after compoundadministration) were analyzed either for acetylcholine or for serotoninby HPLC and electrochemical detection.

Microdialysate Acetylcholine Levels

Acute, single administration of Compound MM (30 mg/kg, p.o.) did notchange ACh release under resting conditions. Challenging conditions asthe transfer from home cage to novel cage, and back to home cageresulted in stimulation of ACh release (see FIGS. 6 a, 6 b and 6 c).Single administration of Compound MM did not induce any furtherstimulation of ACh release, neither in the cortex nor in thehippocampus.

Microdialysatc Serotonin Levels

Single administration of Compound MM (30 mg/kg, p.o.) resulted in along-lasting increase of serotonin (5-HT) levels in the medialprefrontal cortex and in the hippocampus. This is a feature shared bymarketed anti-depressive drugs and might indicate the potential use for11β-HSD1 inhibitors as antidepressants/anxiolytic drugs. These findingsremain to be confirmed by (i) investigating 11β-HSD1 inhibitors fromdifferent chemotype(s) in selected microdialysis studies and/or (ii) inanimal models of depression/anxiety. Additionally, these resultsdifferentiate 11β-HSD-1 inhibition from acetylcholine esteraseinhibition, the current therapeutic principle for symptomatic treatmentof Alzheimer's disease.

Effects of HSD-1 Inhibitors on Monkey Ex Vivo HSD1 Activity

Compound KK demonstrated potent ex vivo inhibition of monkey brain, fatand liver 2.5 and 16 hours following a single oral 10 mg/kg dose.Harvested tissues (approximately 150 mg) were minced into small, 2 mmpieces in the presence of 5× volume of incubation buffer. Cortisone atfinal concentrations of 0, 3, 10 or 30 μM was added to each well. Cellculture plates with tissues were incubated at 37° C. for three hours.Two-hundred μL of tissue culture supernatant was then removed and spunat 1000 rpm in an Eppindorf tube, and then 100 μL of resultingsupernatant was aliquotted into two tubes for LCMS analysis of cortisol.Results are indicated as & vehicle control activity in the table below:

TABLE 3 HSD-1 Ex Vivo Activity in Cynomolgus Monkeys Following a Single10 mg/kg Oral Dose of Compound KK Tissue Time Mean % Veh Control Liver2.5 hours  38% Mesenteric Fat 2.5 hours  90% Liver 16 hours  9%Mesenteric Fat 16 hours 50% Cerebral Cortex 16 hours 30% Hippocampus 16hours 42% N = 3/groupBiochemical Mechanism

Glucocorticoids are steroid hormones that play an important role inregulating multiple physiological processes in a wide range of tissuesand organs. For example, glucocorticoids are potent regulators ofglucose and lipid metabolism. Excess glucocorticoid action may lead toinsulin resistance, type 2 diabetes, dyslipidemia, visceral obesity andhypertension. Cortisol is the major active and cortisone is the majorinactive form of glucocorticoids in humans, while corticosterone anddehydrocorticosterone are the major active and inactive forms inrodents.

Previously, the main determinants of glucocorticoid action were thoughtto be the circulating hormone concentration and the density ofglucocorticoid receptors in the target tissues. In the last decade, itwas discovered that tissue glucocorticoid levels may also be controlledby 11β-hydroxysteroid dehydrogenases enzymes (11β-HSDs). There are two11β-HSD isozymes which have different substrate affinities andcofactors. The 11β-hydroxysteroid dehydrogenases type 1 enzyme(11β-HSD-1) is a low affinity enzyme with K_(m) for cortisone in themicromolar range that prefers NADPH/NADP⁺ (nicotinamide adeninedinucleotide) as cofactors. 11β-HSD-1 is widely expressed andparticularly high expression levels are found in liver, brain, lung,adipose tissue and vascular smooth muscle cells. In vitro studiesindicate that 11β-HSD-1 is capable of acting both as a reductase and adehydrogenase. However, many studies have shown that it is predominantlya reductase in vivo and in intact cells. It converts inactive11-ketoglucocorticoids (i.e., cortisone or dehydrocorticosterone) toactive 11-hydroxyglucocorticoids (i.e., cortisol or corticosterone) andtherefore amplifies the glucocorticoid action in a tissue-specificmanner.

With only 20% homology to 11β-HSD-1, the 11β-hydroxysteroiddehydrogenases type 2 enzyme (11β-HSD-2) is a NAD⁺-dependent, highaffinity dehydrogenase with a K_(m) for cortisol in the nanomolar range.11β-HSD-2 is found primarily in mineralocorticoid target tissues, suchas kidney, colon and placenta. Glucocorticoid action is mediated by thebinding of glucocorticoids to receptors, such as mineralocorticoidreceptors and glucocorticoid receptors. Through binding to its receptor,the main mineralocorticoid aldosterone controls the water and saltsbalance in the body. However, the mineralocorticoid receptors have ahigh affinity for both cortisol and aldosterone. 11β-HSD-2 convertscortisol to inactive cortisone, therefore preventing the non-selectivemineralocorticoid receptors from being exposed to high levels ofcortisol. Mutations in the gene encoding 11β-HSD-2 cause ApparentMineralocorticoid Excess Syndrome (AME), which is a congenital syndromeresulting in hypokaleamia and severe hypertension. AME Patients haveelevated cortisol levels in mineralocorticoid target tissues due toreduced 11β-HSD-2 activity. The AME symptoms may also be induced byadministration of 11β-HSD-2 inhibitor, glycyrrhetinic acid. The activityof 11β-HSD-2 in placenta is probably important for protecting the fetusfrom excess exposure to maternal glucocorticoids, which may result inhypertension, glucose intolerance and growth retardation. Due to thepotential side effects resulting from 11β-HSD-2 inhibition, the presentinvention describes selective 11β-HSD-1 inhibitors.

Glucocorticoid levels and/or activity may contribute to numerousdisorders, including Type II diabetes, obesity, dyslipidemia, insulinresistance and hypertension. Administration of the compounds of thepresent invention decreases the level of cortisol and other11β-hydroxysteroids in target tissues, thereby reducing the effects ofglucucocrticoid activity in key target tissues. The present inventioncould be used for the treatment, control, amelioration, prevention,delaying the onset of or reducing the risk of developing the diseasesand conditions that are described herein.

Since glucocorticoids are potent regulators of glucose and lipidmetabolism, glucocorticoid action may contribute or lead to insulinresistance, type 2 diabetes, dyslipidemia, visceral obesity andhypertension. For example, cortisol antagonizes the insulin effect inliver resulting in reduced insulin sensitivity and increasedgluconeogenesis. Therefore, patients who already have impaired glucosetolerance have a greater probability of developing type 2 diabetes inthe presence of abnormally high levels of cortisol. Previous studies (B.R. Walker et al., J. of Clin. Endocrinology and Met., 80: 3155-3159,1995) have demonstrated that administration of non-selective 11β-HSD-1inhibitor, carbenoxolone, improves insulin sensitivity in humans.Therefore, administration of a therapeutically effective amount of an11β-HSD-1 inhibitor may treat, control, ameliorate, delay, or preventthe onset of type 2 diabetes.

Administration of glucocorticoids in vivo has been shown to reduceinsulin secretion in rats (B. Billaudel et al., Horm. Metab. Res. 11:555-560, 1979). It has also been reported that conversion ofdehydrocorticosterone to corticosterone by 11β-HSD-1 inhibits insulinsecretion from isolated murine pancreatic β cells. (B. Davani et al., J.Biol. Chem., 275: 34841-34844, 2000), and that incubation of isolatedislets with an 11β-HSD-1 inhibitor improves glucose-stimulated insulinsecretion (H Orstater et al., Diabetes Metab. Res. Rev. 21: 359-366,2005). Therefore, administration of a therapeutically effective amountof an 11β-HSD-1 inhibitor may treat, control, ameliorate, delay, orprevent the onset of type 2 diabetes by improving glucose-stimulatedinsulin secretion in the pancreas.

Abdominal obesity is closely associated with glucose intolerance (C. T.Montague et al., Diabetes, 49: 883-888, 2000), hyperinsulinemia,hypertriglyceridemia and other factors of metabolic syndrome (also knownas syndrome X), such as high blood pressure, elevated VLDL and reducedHDL. Animal data supporting the role of 11β-HSD-1 in the pathogenesis ofthe metabolic syndrome is extensive (Masuzaki, et al. Science. 294:2166-2170, 2001; Paterson, J. M., et al.; Proc Natl. Acad. Sci. USA.101: 7088-93, 2004; Montague and O'Rahilly. Diabetes. 49: 883-888,2000). Therefore, administration of a therapeutically effective amountof an 11β-HSD-1 inhibitor may treat, control, ameliorate, delay, orprevent the onset of obesity. Long-term treatment with an 11β-HSD-1inhibitor may also be useful in delaying the onset of obesity, orperhaps preventing it entirely if the patients use an 11β-HSD-1inhibitor in combination with controlled diet, exercise, or incombination or sequence with other pharmacological approaches.

By reducing insulin resistance and/or maintaining serum glucose atnormal concentrations and/or reducing obesity compounds of the presentinvention also have utility in the treatment and prevention ofconditions that accompany Type 2 diabetes and insulin resistance,including the metabolic syndrome or syndrome X, obesity, reactivehypoglycemia, and diabetic dyslipidemia.

11β-HSD-1 is present in multiple tissues, including vascular smoothmuscle, where local glucocorticoid levels that are thought to increaseinsulin resistance, leading to reductions in nitric oxide production,and potentiation of the vasoconstrictive effects of both catecholaminesand angiotensin II (M. Pirpiris et al., Hypertension, 19:567-574, 1992,C. Kornel et al., Steroids, 58: 580-587, 1993, B. R. Walker and B. C.Williams, Clin. Sci. 82:597-605, 1992; Hodge, G. et al Exp. Physiol 87:1-8, 2002). High levels of cortisol in tissues where themineralocorticoid receptor is present may lead to hypertension, asobserved in Cushing's patients (See, D. N. Orth, N. Engl. J. Med.332:791-803, 1995, M. Boscaro, et al., Lancet, 357: 783-791, 2001, X.Bertagna, et al, Cushing's Disease. In: Melmed. S., Ed. The Pituitary.2^(nd) ed. Malden, M A: Blackwell; 592-612, 2002). Transgenic miceoverexpressing 11β-HSD-1 in liver and fat are also hypertensive, aphenotype believed to result from glucocorticoid activation of the reninangiotensin system (Paterson, J. M. et al, PNAS. 101: 7088-93, 2004;Masuzaki, H. et al, J. Clin. Invest. 112: 83-90, 2003). Therefore,administration of a therapeutically effective dose of an 11β-HSD-1inhibitor may treat, control, ameliorate, delay, or prevent the onset ofhypertension.

Cushing's syndrome is a life-threatening metabolic disordercharacterized by sustained and elevated glucocorticoid levels caused bythe endogenous and excessive production of cortisol from the adrenalglands. Typical Cushingoid characteristics include central obesity,diabetes and/or insulin resistance, moon face, buffalo hump, skinthinning, dyslipidemia, osteoporosis, reduced cognitive capacity,dementia, hypertension, sleep deprivation, and atherosclerosis amongothers (Principles and Practice of Endocrinology and Metabolism. Editedby Kenneth Becker, Lippincott Williams and Wilkins Publishers,Philadelphia, 2001; pg 723-8). The same characteristics can also arisefrom the exogenous administration of high doses of exogenousglucocorticoids, such as prednisone or dexamethasone, as part of ananti-inflammatory treatment regimen. Endogenous Cushings typicallyevolves from pituitary hyperplasia, some other ectopic source of ACTH,or from an adrenal carcinoma or nodular hyperplasia. Administration of atherapeutically effective dose of an 11β-HSD-1 inhibitor may reducelocal glucocorticoid concentrations and therefore treat, control,ameliorate, delay, or prevent the onset of Cushing's disease and/orsimilar symptoms arising from glucocorticoid treatment.

11β-HSD-1 is expressed in mammalian brain, and published data indicatesthat glucocorticoids may cause neuronal degeneration and dysfunction,particularly in the aged (de Quervain et al.; Hum Mol. Genet. 13: 47-52,2004; Belanoff et al. J. Psychiatr Res. 35: 127-35, 2001). Evidence inrodents and humans suggests that prolonged elevation of plasmaglucocorticoid levels impairs cognitive function that becomes moreprofound with aging. (Issa, A. M. et al. J. Neurosci. 10: 3247-54, 1990;Lupien, S. J et al. Nat. Neurosci. 1: 69-73, 1998; Yau, J. L. W. et alProc Natl Acad Sci USA. 98: 4716-4712, 2001). Thekkapat et al hasrecently shown that 11β-HSD-1 mRNA is expressed in human hippocampus,frontal cortex and cerebellum, and that treatment of elderly diabeticindividuals with the non-selective HSD1/2 inhibitor carbenoxoloneimproved verbal fluency and memory (Proc Natl Acad Sci USA. 101: 6743-9,2004). Additional CNS effects of glucocorticoids includeglucocorticoid-induced acute psychosis which is of major concern tophysicians when treating patients with these steroidal agents (Wolkowitzet al.; Ann NY Acad. Sci. 1032: 191-4, 2004). Conditional mutagenesisstudies of the glucocorticoid receptor in mice have also providedgenetic evidence that reduced glucocorticoid signaling in the brainresults in decreased anxiety (Tronche, F. et al. (1999) Nature Genetics23: 99-103). Therefore, it is expected that potent, selective 11β-HSD-1inhibitors would treat, control, ameliorate, delay, or prevent the onsetof cognitive decline, dementia, steroid-induced acute psychosis,depression, and/or anxiety.

In Cushing's patients, excess cortisol levels contributes to thedevelopment of hypertension, dyslipidemia, insulin resistance, andobesity, conditions characteristic of metabolic syndrome (Orth, D. N. etal N. Engl. J. Med. 332:791-803, 1995; Boscaro, M. et al., Lancet, 357:783-791, 2001, Bertagna, X. et al, Cushing's Disease. In: Melmed S., Ed.The Pituitary. 2^(nd) ed. Malden, M A: Blackwell; 592-612, 2002).Hypertension and dyslipidemia are also associated with development ofatherosclerosis. 11β-HSD-1 knockout mice are resistant to thedyslipidemic effects of a high fat diet and have an improved lipidprofile vs wild type controls (Morton N. M. et al, JBC, 276:41293-41300, 2001), and mice which overexpress 11β-HSD-1 in fat exhibitthe dyslipidemic phenotype characteristic of metabolic syndrome,including elevated circulating free fatty acids, and triglycerides(Masuzaki, H., et al Science. 294: 2166-2170, 2001). Administration of aselective 11β-HSD-1 inhibitor has also been shown to reduce elevatedplasma triglycerides and free fatty acids in mice on a high fat diet,and significantly reduce aortic content of cholesterol esters, andreduce progression of atherosclerotic plaques in mice(Hermanowski-Vosatka, A. et al. J. Exp. Med. 202: 517-27, 2005). Theadministration of a therapeutically effective amount of an 11β-HSD-1inhibitor would therefore be expected to treat, control, ameliorate,delay, or prevent the onset of dyslipidemia and/or atherosclerosis.

Glucocorticoids are known to cause a variety of skin related sideeffects including skin thinning, and impairment of wound healing(Anstead, G. Adv Wound Care. 11: 277-85, 1998; Beer, et al.; Vitam Horm.59: 217-39, 2000). 11β-HSD-1 is expressed in human skin fibroblasts, andit has been shown that the topical treatment with the non-selectiveHSD1/2 inhibitor glycerrhetinic acid increases the potency of topicallyapplied hydrocortisone in a skin vasoconstrictor assay (Hammami, M M,and Siiteri, P K. J. Clin. Endocrinol. Metab. 73: 326-34, 1991).Advantageous effects of selective 11β-HSD-1 inhibitors such as BVT.2733on wound healing have also been reported (WO 2004/11310). High levels ofglucocorticoids inhibit blood flow and formation of new blood vessels tohealing tissues. In vitro and in vivo models of angiogenesis have shownthat systemic antagonism with the glucocorticoid receptor RU-486enhances angiogenesis in subcutaneous sponges as well as in mousemyocardium following coronary artery ligation (Walker, et al, PNAS, 102:12165-70, 2005). 11β-HSD-1 knockout mice also showed enhancedangiogenesis in vitro and in vivo within sponges, wounds, and infractedmyocardium. It is therefore expected that potent, selective 11β-HSD-1inhibitors would treat, control, ameliorate, delay, or prevent the onsetof skin thinning and/or promote wound healing and/or angiogenesis.

Although cortisol is an important and well-recognized anti-inflammatoryagent (J. Baxer, Pharmac. Ther., 2:605-659, 1976), if present in largeamount it also has detrimental effects. In certain disease states, suchas tuberculosis, psoriasis and stress in general, high glucocorticoidactivity shifts the immune response to a humoral response, when in facta cell based response may be more beneficial to patients. Inhibition of11β-HSD-1 activity may reduce glucocorticoid levels, thereby shiftingthe immuno response to a cell based response. (D. Mason, ImmunologyToday, 12: 57-60, 1991, G. A. W. Rook, Baillier's Clin. Endocrinol.Metab. 13: 576-581, 1999). Therefore, administration of 11β-HSD-1specific inhibitors could treat, control, ameliorate, delay, or preventthe onset of tuberculosis, psoriasis, stress, and diseases or conditionswhere high glucocorticoid activity shifts the immune response to ahumoral response.

One of the more significant side effects associated with topical andsystemic glucocorticoid therapy is glaucoma, resulting in seriousincreases in intraocular pressure, with the potential to result inblindness (Armaly et al.; Arch Ophthalmol. 78: 193-7, 1967; Stokes etal.; Invest Ophthalmol Vis Sci. 44: 5163-7, 2003;). The cells thatproduce the majority of aqueous humor in the eye are the nonpigmentedepithelial cells (NPE). These cells have been demonstrated to express11β-HSD-1, and consistent with the expression of 11β-HSD-1, is thefinding of elevated ratios of cortisol:cortisone in the aqueous humor(Rauz et al. Invest Ophthalmol V is Sci. 42: 2037-2042, 2001).Furthermore, it has been shown that patients who have glaucoma, but whoare not taking exogenous steroids, have elevated levels of cortisol vs.cortisone in their aqueous humor (Rauz et al. QJM. 96: 481-490, 2003.)Treatment of patients with the nonselective HSD1/2 inhibitorcarbenoxolone for 4 or 7 days significantly lowered intraocular pressureand local cortisol generation within the eye (Rauz et al.; QJM. 96:481-490, 2003.). It is therefore expected that potent, selective11β-HSD-1 inhibitors would treat, control, ameliorate, delay, or preventthe onset of glaucoma.

Glucocorticoids (GCs) are known to increase bone resorption and reducebone formation in mammals (Turner et al. Calcif Tissue Int. 54: 311-5,1995; Lane, N E et al. Med Pediatr Oncol. 41: 212-6, 2003). 11β-HSD-1mRNA expression and reductase activity have been demonstrated in primarycultures of human osteoblasts in homogenates of human bone (Bland etal.; J. Endocrinol. 161: 455-464, 1999; Cooper et al.; Bone, 23:119-125, 2000). In surgical explants obtained from orthopedicoperations, 11β-HSD-1 expression in primary cultures of osteoblasts wasfound to be increased approximately 3-fold between young and old donors(Cooper et al.; J. Bone Miner Res. 17: 979-986, 2002). Glucocorticoids,such as prednisone and dexamethasone, are also commonly used to treat avariety of inflammatory conditions including arthritis, inflammatorybowl disease, and asthma. These steroidal agents have been shown toincrease expression of 11β-HSD-1 mRNA and activity in human osteoblasts(Cooper et al.; J. Bone Miner Res. 17: 979-986, 2002). These studiessuggest that 11β-HSD-1 plays a potentially important role in thedevelopment of bone-related adverse events as a result of excessiveglucocorticoid levels or activity. Bone samples taken from healthy humanvolunteers orally dosed with the non-selective HSD1/2 inhibitorcarbenoxolone showed a significant decrease in markers of boneresorption (Cooper et al.; Bone. 27: 375-81, 2000). It is thereforeexpected that potent, selective 11β-HSD-1 inhibitors would treat,control, ameliorate, delay, or prevent the onset of conditions ofglucocorticoid-induced or age-dependent osteoporosis

The following diseases, disorders and conditions can be treated,controlled, prevented or delayed, by treatment with the compounds ofthis invention: (1) hyperglycemia, (2) low glucose tolerance, (3)insulin resistance, (4) lipid disorders, (5) hyperlipidemia, (6)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12), atherosclerosis and its sequelae, (13)vascular restensosis, (14) pancreatitis, (15) obdominal obesity, (16)neurodegenerative disease, (17) retinopathy, (18) nephropather, (19),neuropathy, (20) hypertension and other disorders where insulinresistance is a component, and (21) other diseases, disorders, andconditions that can benefit from reduced local glucocorticoid levels.

Neuronal Effects of 11β-HSD Inhibitors

Studies have shown that in homogenates of hippocampus, bothdehydrogenation and reduction occur (V. Lakshmi, et al., Endocrinol.,128, 1741-1748, 1991) and that 11β-HSD-1 is expressed in mammalianbrain, and published data indicates that glucocorticoids may causeneuronal degeneration and dysfunction (de Quervain et al., Hum Mol.Genet. 13: 47-52, 2004; Belanoff et al., J. Psychiatr Res., 35: 127-35,2001). Several studies have demonstrated 11β-HSD activity,immunoreactivity and mRNA expression in hippocampal neurons (M-P Moisan,et al., Endocrinol 127, 1450-1455, 1990; V. Lakshmi, et al.,Endocrinol., 128, 1741-1748, 1991; R R Sakai, et al., JNeuroendocrinol., 4, 101-106, 1992). Administration of 11β-HSDinhibitors alters functional activity in the hippocampus in vivo (J RSeckl, et al., J Endocrinol 136, 471-477, 1993). Evidence in rodents andhumans suggests that prolonged elevation of plasma glucocorticoid levelsimpairs cognitive function that becomes more profound with aging (A. M.Issa et al., 0.1. Neurosci., 10: 3247-3254, 1990, S. J. Lupien, et. al.,Nat. Neurosci., 1:69-73 1998, J. L. Yau et al., Neuroscience, 66:571-581, 1995). Chronic excessive cortisol levels in the brain mayresult in neuronal loss and neuronal dysfunction. (See, D. S. Kerr etal., Psychobiology 22: 123-133, 1994, C. Woolley, Brain Res. 531:225-231, 1990, P. W. Landfield, Science, 272: 1249-1251, 1996).Furthermore, glucocorticoid-induced acute psychosis exemplifies a morepharmacological induction of this response, and is of major concern tophysicians when treating patients with these steroidal agents (Wolkowitzet al., Ann NY Acad. Sci. 1032: 191-4, 2004). Thekkapat et al haverecently shown that 11β-HSD-1 mRNA is expressed in human hippocampus,frontal cortex and cerebellum, and that treatment of elderly diabeticindividuals with the non-selective 11β-HSD-1 and 11β-HSD-2 inhibitorcarbenoxolone improved verbal fluency and memory (Proc Natl Acad SciUSA. 101: 6743-9, 2004). In addition, Walker et al have examined 11β-HSDactivity and its function in primary cultures of fetal hippocampus cells(U.S. Pat. No. 7,122,531; U.S. Pat. No. 7,087,400; Rajan V, et al., J.Neurosci., 16, 65-70 (1996)), the contents of which are incorporatedherein by reference.

Therefore, the CNS diseases, disorders and conditions can be treated,controlled, prevented or delayed, by treatment with the compounds ofthis invention. Administration of a therapeutic dose of an 11β-HSD-1inhibitor may reduce, ameliorate, control and/or prevent disorders suchas the cognitive impairment associated with aging, neuronal dysfunction,dementia, steroid-induced acute psychosis, decline in cognitive functionin Alzheimer's and associated dementias, cognitive deficits associatedwith aging and neurodegeneration, dementia, senile dementia, AIDSdementia, depression, major depressive disorder, psychotic depression,treatment resistant depression, anxiety, panic disorder, post traumaticstress disorder, depression in Cushing's syndrome, steroid-induced acutepsychosis, cognitive deficits associated with diabetes, attentiondeficit disorder in general, attention deficit hyperactivity disorder(ADHD), mild cognitive impairment, and schizophrenia.

HSD-1 related disorders include, but are not limited to, non-insulindependent type 2 diabetes, insulin resistance, obesity, lipid disorders,metabolic syndrome, hyperglycemia, low glucose tolerance,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDLlevels, high LDL levels, atherosclerosis and its sequelae, vascularrestensosis, pancreatitis, abdominal obesity, retinopathy, nephropather,neuropathy, hypertension, other disorders where insulin resistance is acomponent, cognitive impairment associated with aging, neuronaldysfunction, dementia, steroid-induced acute psychosis, decline incognitive function in Alzheimer's disease and associated dementias,cognitive deficits associated with aging and neurodegeneration,dementia, senile dementia, AIDS dementia, anxiety, panic disorder, posttraumatic stress disorder, steroid-induced acute psychosis, cognitivedeficits associated with diabetes, attention deficit disorder ingeneral, attention deficit hyperactivity disorder (ADHD), mild cognitiveimpairment, schizophrenia, and depression including major depressivedisorder, psychotic depression, depression in Cushing's syndrome, andtreatment resistant depression.

Accordingly, an embodiment is a method of inhibiting11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprisingadministering to a mammal, a therapeutically effective amount of acompound of formula (I). Another embodiment is treating orprophylactically treating the above disorders in a mammal. The disordersmay be mediated by excessive glucocorticoid action in a mammal.

Therapeutic Compositions-Administration-Dose Ranges

Therapeutic compositions of the present compounds comprise an effectiveamount of the same formulated with one or more therapeutically suitableexcipients. The term “therapeutically suitable excipient,” as usedherein, generally refers to pharmaceutically suitable, solid, semi-solidor liquid fillers, diluents, encapsulating material, formulationauxiliary and the like. Examples of therapeutically suitable excipientsinclude, but are not limited to, sugars, cellulose and derivativesthereof, oils, glycols, solutions, buffers, colorants, releasing agents,coating agents, sweetening agents, flavoring agents, perfuming agentsand the like. Such therapeutic compositions may be administeredparenterally, intracisternally, orally, rectally, intraperitoneally orby other dosage forms known in the art.

Liquid dosage forms for oral administration include, but are not limitedto, emulsions, microemulsions, solutions, suspensions, syrups andelixirs. Liquid dosage forms may also contain diluents, solubilizingagents, emulsifying agents, inert diluents, wetting agents, emulsifiers,sweeteners, flavorants, perfuming agents and the like.

Injectable preparations include, but are not limited to, sterile,injectable, aqueous, oleaginous solutions, suspensions, emulsions andthe like. Such preparations may also be formulated to include, but arenot limited to, parenterally suitable diluents, dispersing agents,wetting agents, suspending agents and the like. Such injectablepreparations may be sterilized by filtration through abacterial-retaining filter. Such preparations may also be formulatedwith sterilizing agents that dissolve or disperse in the injectablemedia or other methods known in the art.

The absorption of the compounds of the present invention may be delayedusing a liquid suspension of crystalline or amorphous material havingpoor water solubility. The rate of absorption of the compounds generallydepends upon the rate of dissolution and crystallinity. Delayedabsorption of a parenterally administered compound may also beaccomplished by dissolving or suspending the compound in oil. Injectabledepot dosage forms may also be prepared by microencapsulating the samein biodegradable polymers. The rate of drug release may also becontrolled by adjusting the ratio of compound to polymer and the natureof the polymer employed. Depot injectable formulations may also preparedby encapsulating the compounds in liposomes or microemulsions compatiblewith body tissues.

Solid dosage forms for oral administration include, but are not limitedto, capsules, tablets, gels, pills, powders, granules and the like. Thedrug compound is generally combined with at least one therapeuticallysuitable excipient, such as carriers, fillers, extenders, disintegratingagents, solution retarding agents, wetting agents, absorbents,lubricants and the like. Capsules, tablets and pills may also containbuffering agents. Suppositories for rectal administration may beprepared by mixing the compounds with a suitable non-irritatingexcipient that is solid at ordinary temperature but fluid in the rectum.

The present drug compounds may also be microencapsulated with one ormore excipients. Tablets, dragees, capsules, pills and granules may alsobe prepared using coatings and shells, such as enteric and release orrate controlling polymeric and nonpolymeric materials. For example, thecompounds may be mixed with one or more inert diluents. Tableting mayfurther include lubricants and other processing aids. Similarly,capsules may contain opacifying agents that delay release of thecompounds in the intestinal tract.

Transdermal patches have the added advantage of providing controlleddelivery of the present compounds to the body. Such dosage forms areprepared by dissolving or dispensing the compounds in suitable medium.Absorption enhancers may also be used to increase the flux of thecompounds across the skin. The rate of absorption may be controlled byemploying a rate controlling membrane. The compounds may also beincorporated into a polymer matrix or gel.

For a given dosage form, disorders of the present invention may betreated, prophylatically treated, or have their onset delayed in apatient by administering to the patient a therapeutically effectiveamount of compound of the present invention in accordance with asuitable dosing regimen. In other words, a therapeutically effectiveamount of any one of compounds of formulas (I) is administered to apatient to treat and/or prophylatically treat disorders modulated by the11-beta-hydroxysteroid dehydrogenase type 1 enzyme. The specifictherapeutically effective dose level for a given patient population maydepend upon a variety of factors including, but not limited to, thespecific disorder being treated, the severity of the disorder; theactivity of the compound, the specific composition or dosage form, age,body weight, general health, sex, diet of the patient, the time ofadministration, route of administration, rate of excretion, duration ofthe treatment, drugs used in combination, coincidental therapy and otherfactors known in the art.

The present invention also includes therapeutically suitable metabolitesformed by in vivo biotransformation of any of the compounds of formula(I). The term “therapeutically suitable metabolite”, as used herein,generally refers to a pharmaceutically active compound formed by the invivo biotransformation of compounds of formula (I). For example,pharmaceutically active metabolites include, but are not limited to,compounds made by adamantane hydroxylation or polyhydroxylation of anyof the compounds of formulas (I). A discussion of biotransformation isfound in Goodman and Gilman's, The Pharmacological Basis ofTherapeutics, seventh edition, MacMillan Publishing Company, New York,N.Y., (1985).

The total daily dose (single or multiple) of the drug compounds of thepresent invention necessary to effectively inhibit the action of11-beta-hydroxysteroid dehydrogenase type 1 enzyme may range from about0.01 mg/kg/day to about 50 mg/kg/day of body weight and more preferablyabout 0.1 mg/kg/day to about 25 mg/kg/day of body weight. Treatmentregimens generally include administering from about 10 mg to about 1000mg of the compounds per day in single or multiple doses.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed aspects will be apparent to those skilledin the art. Such changes and modifications, including without limitationthose relating to the chemical structures, substituents, derivatives,intermediates, syntheses, formulations and/or methods of use of theinvention, may be made without departing from the spirit and scopethereof.

What is claimed is:
 1. A method for treating a patient suffering from adisorder selected from the group consisting of neuropathy, neuronaldysfunction, decline in cognitive function in Alzheimer's disease andassociated dementias, attention deficit disorder in general, attentiondeficit hyperactivity disorder (ADHD), mild cognitive impairment,steroid-induced acute psychosis, schizophrenia, and combinationsthereof, comprising administering to the patient an effective amount ofa compound of formula (I), or a pharmaceutically acceptable salt, or acombination thereof,

wherein one of A¹, A², A³ and A⁴ is selected from the group consistingof alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl,heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl,carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl,—S(O)₂—N(R⁵R⁶), —NR⁷—[C(R⁸R⁹)]_(n)—C(O)—R¹⁰,—O—[C(R¹¹R¹²)]_(p)—C(O)—R¹³, —OR^(14a), —N(R¹⁵R¹⁶), —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), —C(R²⁰R²¹)—OR²², —C(R²³R²⁴)—N(R²⁵R²⁶), and heterocycle,with the exception that 5 membered heterocycles may not contain twooxygen atoms, and the remaining members of the group consisting of A¹,A², A³ and A⁴ are each individually selected from the group consistingof hydrogen, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl,cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl,arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl,aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxyalkyl, —S(O)₂—N(R⁵R⁶),—NR⁷—[C(R⁸R⁹)]_(n)—C(O)—R¹⁰, —O—[C(R¹¹R¹²)]_(p)—C(O)—R¹³, —OR^(14b),—N(R¹⁵R¹⁶), —CO₂R¹⁷, —C(O)—N(R¹⁸R¹⁹), —C(R²⁰R²¹)—OR²² and—C(R²³R²⁴)—N(R²⁵R²⁶); n is 0 or 1; p is 0 or 1; D is selected from thegroup consisting of a bond, —C(R²⁷R²⁸)—X— and —C(R²⁷R²⁸)—C(R²⁹R³)—X—; Eis selected from the group consisting of cycloalkyl, alkyl, aryl,heteroaryl and heterocycle, wherein the heteroaryl is appended to theparent molecular moiety through an available carbon atom, or R⁴ and Etogether with the atoms to which they are attached form a ring selectedfrom the group consisting of cycloalkyl and heterocycle; X is selectedfrom the group consisting of a bond, —N(R³¹)—, —O—, —S—, —S(O)— and—S(O)₂—; R¹ is selected from the group consisting of hydrogen and alkyl;R² is selected from the group consisting of hydrogen, alkyl andcycloalkyl; R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl,cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycle and heterocyclealkyl, or R³ and R⁴ together with the atom towhich they are attached form a ring selected from the group consistingof cycloalkyl and heterocycle; R⁵ and R⁶ are each independently selectedfrom the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl,alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl,cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl,heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl,heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl,heterocycleoxy, heterocyclesulfonyl and hydroxy, or R⁵ and R⁶ togetherwith the atom to which they are attached form a heterocycle; R⁷ isselected from the group consisting of hydrogen, alkyl, carboxyalkyl,cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy,alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,heterocyclealkyl and heterocycleoxyalkyl; R⁸ and R⁹ are eachindependently selected from the group consisting of hydrogen and alkyl,or R⁸ and R⁹ taken together with the atom to which they are attachedform a ring selected from the group consisting of cycloalkyl andheterocycle; R¹⁰ is selected from the group consisting of hydrogen,alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and —N(R³²R³³);R¹¹ and R¹² are each independently selected from the group consisting ofhydrogen and alkyl or R¹¹ and R¹² taken together with the atom to whichthey are attached form a ring selected from the group consisting ofcycloalkyl and heterocycle; R¹³ is selected from the group consisting ofhydroxy and —N(R³⁴R³⁵); R^(14a) is selected from the group consisting ofcarboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl; R^(14b) is selected from the group consisting ofhydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl; R¹⁵ and R¹⁶ are each independently selected fromthe group consisting of hydrogen, alkyl, alkylcarbonyl, carboxyalkyl,cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl,heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl,heterocyclesulfonyl, alkylsufonyl, cycloalkylsulfonyl and arylsulfonyl,or R¹⁵ and R¹⁶ together with the atom to which they are attached form aheterocycle; R¹⁷ is selected from the group consisting of hydrogen,alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl,heterocycle, heterocyclealkyl and heterocycleoxyalkyl; R¹⁸ and R¹⁹ areeach independently selected from the group consisting of hydrogen,alkoxy, alkyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl,cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, orR¹⁸ and R¹⁹ together with the atom to which they are attached form aheterocycle; R²⁰, R²¹ and R²² are each independently selected from thegroup consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl,carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heterocycle and heterocyclealkyl; R²³ and R²⁴ are each independentlyselected from the group consisting of hydrogen, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl,carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl,heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle,heterocyclecarbonyl and heterocyclesulfonyl; R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, alkoxy,alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, aryloxy,arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl,cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl,heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle,heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, orR²⁵ and R²⁶ together with the nitrogen to which they are attached form aring selected from the group consisting of heteroaryl and heterocycle;R²⁷ and R²⁸ are each independently selected from the group consisting ofhydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R²⁷ andR²⁸ together with the atom to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle, or R²⁷and R²⁹ together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle, or R²⁸and R⁴ together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle; R²⁹and R³⁰ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy,heteroaryl, heterocycle, and —N(R³⁶R³⁷), or R²⁹ and R³⁰ together withthe atom to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle, or R²⁹ and R⁴ together withthe atoms to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle, or R²⁹ and E together with theatoms to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle; R³¹ is selected from the groupconsisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycle andheteroaryl, or R³¹ and E together with the atom to which they areattached form a ring selected from the group consisting of heteroaryland heterocycle, or R³¹ and R⁴ together with the atoms to which they areattached form a heterocycle; R³² and R³³ are each independently selectedfrom the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl,heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl,arylsulfonyl, and heterocyclesulfonyl, or R³² and R³³ together with theatom to which they are attached form a heterocycle; R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl,aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl,heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl,cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R³⁴ andR³⁵ together with the atom to which they are attached form aheterocycle; and R³⁶ and R³⁷ are each independently selected from thegroup consisting of hydrogen, alkyl and aryl.
 2. The method according toclaim 1, wherein the inhibitor is a therapeutically suitable metaboliteof a compound of formula (I).
 3. The method according to claim 1,wherein the inhibitor is a compound selected from the group consistingof:E-4-{[1-(4-chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylicacid;E-4-[(1-phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylicacid; E-4-(2-methyl-2-phenyl-propionylamino)-adamantane-1-carboxylicacid;E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxylicacid amide;E-4-[(1-phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic acidamide; E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylicacid amide;E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxamide;E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;E-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;E-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[(1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxamide;E-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide;E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;E-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;E-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxamide;E-4-{[2-methyl-2-(4-pyridin-4-ylphenyl)propanoyl]amino}adamantane-1-carboxamide;E-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-1-carboxamide;E-4-[(2-methyl-2-thien-3-ylpropanoyl)amino]adamantane-1-carboxamide;E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamantane-1-carboxamide;E-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2yl]phenyl}propanoyl)amino]adamantane-1-carboxamide;E-4-({[1-(4-methoxyphenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamide;E-4-{[2-(4-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-[5-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopiperidine-3-carboxamide;E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopyrrolidine-3-carboxamide;E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopyrrolidine-3-carboxamide;E-4-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3-carboxamide;E-4-(aminocarbonyl)-2-adamantyl]-1-(3-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3-carboxamide;E-4-({2-methyl-2-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-1-carboxamide;E-4-{[2-(3-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-({2-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxamide;E-4-{[2-methyl-2-(4-pyridin-3-ylphenyl)propanoyl]amino}adamantane-1-carboxamide;4-{[({(E)-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoicacid;E-4-({2-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-1-carboxamide;E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(1-methyl-1-phenylethyl)-2-oxopyrrolidine-3-carboxamide;E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxamide;E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide;E-4-{[2-methyl-2-(1,3-thiazol-2-yl)propanoyl]amino}adamantane-1-carboxamide;E-4-(aminocarbonyl)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpiperidine-3-carboxamide;E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopiperidine-3-carboxamide;E-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(1-benzothien-3-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamide;(E)-4-[(2-methyl-2-pyrazin-2-ylpropanoyl)amino]adamantane-1-carboxamide;N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(2-pyridin-2-ylethyl)pyrrolidine-3-carboxamide;methyl(E)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxylate;(E)-4-({2-methyl-2-[3-(1,3-thiazol-4-ylmethoxy)phenyl]propanoyl}amino)adamantane-1-carboxamide;(E)-4-({2-methyl-2-[6-(methylamino)pyridin-3-yl]propanoyl}amino)adamantane-1-carboxamide;(E)-4-({2-methyl-2-[3-(morpholin-4-ylmethyl)phenyl]propanoyl}amino)adamantane-1-carboxamide;(E)-4-({2-methyl-2-[4-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamantane-1-carboxamide;(E)-4-[(2-{3-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-2-methylpropanoyl)amino]adamantane-1-carboxamide;methyl(E)-4-{[(1-phenylcyclopropyl)carbonyl]amino}adamantane-1-carboxylate;(E)-4-{[2-(6-fluoropyridin-3-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;(E)-N-[3-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;N-[(E)-5-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopiperidine-3-carboxamide;N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-4-ylmethyl)pyrrolidine-3-carboxamide;(E)-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxylicacid;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-phenylcyclopropanecarboxamide;(E)-4-({3-[(5-cyanopyridin-2-yl)oxy]-2,2-dimethylpropanoyl}amino)adamantane-1-carboxamide;N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(1-pyridin-2-ylethyl)pyrrolidine-3-carboxamide;(E)-4-[(2-methyl-3-phenylpropanoyl)amino]adamantane-1-carboxamide;(E)-4-{[2-methyl-2-(6-morpholin-4-ylpyridin-3-yl)propanoyl]amino}adamantane-1-carboxamide;methyl(E)-4-({[1-(4-chlorophenyl)cyclobutyl]carbonyl}amino)adamantane-1-carboxylate;N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-3-ylmethyl)pyrrolidine-3-carboxamide;(E)-4-[(2-methyl-2-{6-[(2-morpholin-4-ylethyl)amino]pyridin-3-yl}propanoyl)amino]adamantane-1-carboxamide;(E)-4-[(2-methyl-2-{4-[(E)-2-pyridin-4-ylvinyl]phenyl}propanoyl)amino]adamantane-1-carboxamide;N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-chlorophenyl)-2-methylpropanamide;(E)-4-({2-methyl-2-[3-(2-morpholin-4-ylethoxy)phenyl]propanoyl}amino)adamantane-1-carboxamide;(E)-4-{[2-(3-cyanopyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;(E)-4-({2-methyl-2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanoyl}amino)adamantane-1-carboxamide;N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide;(E)-N-[4-(aminosulfonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;(E)-4-({2-methyl-2-[4-(pentyloxy)phenyl]propanoyl}amino)adamantane-1-carboxylicacid;(E)-4-({2-methyl-2-[4-(1,3-thiazol-4-ylmethoxy)phenyl]propanoyl}amino)adamantane-1-carboxylicacid;(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(1,3-thiazol-5-ylmethyl)adamantane-1-carboxamide;(E)-4-({2-[4-(benzyloxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxylicacid;(E)-4-{[2-(5-cyanopyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;(E)-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxylicacid;4-[({[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)-1-adamantyl]carbonyl}amino)methyl]benzoicacid;4-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoicacid;3-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoicacid;(E)-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylicacid;(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-4-ylmethyl)adamantane-1-carboxamide;(E)-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylicacid;(E)-N-(2-furylmethyl)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxamide;3-[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)-1-adamantyl]-1H-pyrazole-5-carboxamide;(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-3-ylmethyl)adamantane-1-carboxamide;(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(pyridin-2-ylmethyl)adamantane-1-carboxamide;(E)-4-({2-[4-(cyclohexylmethoxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carboxylicacid;(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}propanoyl)amino]adamantine-1-carboxylicacid; andN-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopyrrolidine-3-carboxamide;or a pharmaceutically acceptable salt, or a combination thereof.
 4. Themethod of claim 1, wherein the patient is a mammal.
 5. The method ofclaim 4, wherein the disorder is mediated by excessive glucocorticoidaction in the mammal.
 6. The method of claim 4, wherein the disorder isdecline in cognitive function in Alzheimer's disease.
 7. The method ofclaim 4, wherein the disorder is attention deficit disorder in general,attention deficit hyperactivity disorder (ADHD), or mild cognitiveimpairment.
 8. The method of claim 4, wherein the disorder isschizophrenia.
 9. A method for treating a patient suffering from adisorder selected from the group consisting of non insulin dependenttype 2 diabetes, insulin resistance, obesity, metabolic syndrome,hypertension, anxiety, major depressive disorder, psychotic depression,treatment resistant depression, panic disorder, post traumatic stressdisorder, depression in Cushing's syndrome, cognitive deficitsassociated with diabetes and cognitive deficits associated with aging,and combinations thereof, comprising administering to the patient aneffective amount of a selective inhibitor of 11-beta-hydroxysteroiddehydrogenase Type 1 enzyme activity, wherein said inhibitor is acompound of formula (I), or a pharmaceutically acceptable salt, or acombination thereof,

wherein one of A¹, A², A³ and A⁴ is selected from the group consistingof alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl,heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl,carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl,—S(O)₂—N(R⁵R⁶), —NR⁷—[C(R⁸R⁹)]_(N)—C(O)—R¹⁰,—O—[C(R¹¹R¹²)]_(p)—C(O)—R¹³, —OR^(14a), —N(R¹⁵R¹⁶), —CO₂R¹⁷,—C(O)—N(R¹⁸R¹⁹), —C(R²⁰R²¹)—OR²², —C(R²³R²⁴)—N(R²⁵R²⁶), and heterocycle,with the exception that 5 membered heterocycles may not contain twooxygen atoms, and the remaining members of the group consisting of A¹,A², A³ and A⁴ are each individually selected from the group consistingof hydrogen, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl,cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl,arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl,aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl,heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxyalkyl, —S(O)₂—N(R⁵R⁶),—NR⁷—[C(R⁸R⁹)]_(n)—C(O)—R¹⁰, —O—[C(R¹¹R¹²)]_(p)—C(O)—R¹³, —OR^(14b),—N(R¹⁵R¹⁶), —CO₂R¹⁷, —C(O)—N(R¹⁸R¹⁹), —C(R²⁰R²¹)—OR²², and—C(R²³R²⁴)—N(R²⁵R²⁶); n is 0 or 1; p is 0 or 1; D is selected from thegroup consisting of a bond, —C(R²⁷R²⁸)—X— and —C(R²⁷R²⁸)—C(R²⁹R³)—X—; Eis selected from the group consisting of cycloalkyl, alkyl, aryl,heteroaryl and heterocycle, wherein the heteroaryl is appended to theparent molecular moiety through an available carbon atom, or R⁴ and Etogether with the atoms to which they are attached form a ring selectedfrom the group consisting of cycloalkyl and heterocycle; X is selectedfrom the group consisting of a bond, —N(R³¹)—, —O—, —S—, —S(O)— and—S(O)₂—; R¹ is selected from the group consisting of hydrogen and alkyl;R² is selected from the group consisting of hydrogen, alkyl andcycloalkyl; R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl,cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycle and heterocyclealkyl, or R³ and R⁴ together with the atom towhich they are attached form a ring selected from the group consistingof cycloalkyl and heterocycle; R⁵ and R⁶ are each independently selectedfrom the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl,alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl,cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl,heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl,heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl,heterocycleoxy, heterocyclesulfonyl and hydroxy, or R⁵ and R⁶ togetherwith the atom to which they are attached form a heterocycle; R⁷ isselected from the group consisting of hydrogen, alkyl, carboxyalkyl,cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy,alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,heterocyclealkyl and heterocycleoxyalkyl; R⁸ and R⁹ are eachindependently selected from the group consisting of hydrogen and alkyl,or R⁸ and R⁹ taken together with the atom to which they are attachedform a ring selected from the group consisting of cycloalkyl andheterocycle; R¹⁰ is selected from the group consisting of hydrogen,alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle,heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and —N(R³²R³³);R¹¹ and R¹² are each independently selected from the group consisting ofhydrogen and alkyl or R¹¹ and R¹² taken together with the atom to whichthey are attached form a ring selected from the group consisting ofcycloalkyl and heterocycle; R¹³ is selected from the group consisting ofhydroxy and —N(R³⁴R³⁵); R^(14a) is selected from the group consisting ofcarboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl; R^(14b) is selected from the group consisting ofhydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heterocycle, heterocyclealkyl andheterocycleoxyalkyl; R¹⁵ and R¹⁶ are each independently selected fromthe group consisting of hydrogen, alkyl, alkylcarbonyl, carboxyalkyl,cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl,heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl,heterocyclesulfonyl, alkylsufonyl, cycloalkylsulfonyl and arylsulfonyl,or R¹⁵ and R¹⁶ together with the atom to which they are attached form aheterocycle; R¹⁷ is selected from the group consisting of hydrogen,alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl,heterocycle, heterocyclealkyl and heterocycleoxyalkyl; R¹⁸ and R¹⁹ areeach independently selected from the group consisting of hydrogen,alkoxy, alkyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl,cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl,heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, orR¹⁸ and R¹⁹ together with the atom to which they are attached form aheterocycle; R²⁰, R²¹ and R²² are each independently selected from thegroup consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl,carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl,heterocycle and heterocyclealkyl; R²³ and R²⁴ are each independentlyselected from the group consisting of hydrogen, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl,carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl,heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle,heterocyclecarbonyl and heterocyclesulfonyl; R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, alkoxy,alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, aryloxy,arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl,cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl,heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle,heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, orR²⁵ and R²⁶ together with the nitrogen to which they are attached form aring selected from the group consisting of heteroaryl and heterocycle;R²⁷ and R²⁸ are each independently selected from the group consisting ofhydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R²⁷ andR²⁸ together with the atom to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle, or R²⁷and R²⁹ together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle, or R²⁸and R⁴ together with the atoms to which they are attached form a ringselected from the group consisting of cycloalkyl and heterocycle; R²⁹and R³⁰ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy,heteroaryl, heterocycle, and —N(R³⁶R³⁷), or R²⁹ and R³⁰ together withthe atom to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle, or R²⁹ and R⁴ together withthe atoms to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle, or R²⁹ and E together with theatoms to which they are attached form a ring selected from the groupconsisting of cycloalkyl and heterocycle; R³¹ is selected from the groupconsisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycle andheteroaryl, or R³¹ and E together with the atom to which they areattached form a ring selected from the group consisting of heteroaryland heterocycle, or R³¹ and R⁴ together with the atoms to which they areattached form a heterocycle; R³² and R³³ are each independently selectedfrom the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy,aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl,heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl,arylsulfonyl, and heterocyclesulfonyl, or R³² and R³³ together with theatom to which they are attached form a heterocycle; R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen, alkyl,carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl,aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl,heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl,cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R³⁴ andR³⁵ together with the atom to which they are attached form aheterocycle; and R³⁶ and R³⁷ are each independently selected from thegroup consisting of hydrogen, alkyl and aryl.
 10. The method accordingto claim 9, wherein the inhibitor is a compound selected from the groupconsisting of:E-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-1-carboxamide;E-4-[(2-methyl-2-thien-3-ylpropanoyl)amino]adamantane-1-carboxamide;E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamantane-1-carboxamide;4-{[({(E)-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]-1-adamantyl}carbonyl)amino]methyl}benzoicacid;E-4-{[2-methyl-2-(1,3-thiazol-2-yl)propanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(1-benzothien-3-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;E-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;andE-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamide;or a pharmaceutically acceptable salt, or a combination thereof.
 11. Themethod of claim 9, wherein the patient is a mammal.
 12. The method ofclaim 11, wherein the disorder is mediated by excessive glucocorticoidaction in a mammal.
 13. The method of claim 11, wherein the disorder isselected from the group consisting of non insulin dependent type 2diabetes, insulin resistance, obesity, metabolic syndrome, andhypertension.
 14. The method of claim 11, wherein the disorder iscognitive deficits associated with aging.
 15. The method of claim 11,wherein the disorder is depression.
 16. The method of claim 15, whereinthe depression is major depressive disorder, psychotic depression,depression in Cushing's syndrome, or treatment resistant depression. 17.The method of claim 11, wherein the disorder is anxiety, panic disorder,or post traumatic stress disorder.
 18. The method of claim 11, whereinthe disorder is cognitive deficits associated with diabetes.